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Carbon Dioxide Changes during High-flow Nasal Oxygenation in Apneic Patients: A Single-center Randomized Controlled Noninferiority Trial.
Riva, T, Greif, R, Kaiser, H, Riedel, T, Huber, M, Theiler, L, Nabecker, S
Anesthesiology. 2022;(1):82-92
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Abstract
BACKGROUND Anesthesia studies using high-flow, humidified, heated oxygen delivered via nasal cannulas at flow rates of more than 50 l · min-1 postulated a ventilatory effect because carbon dioxide increased at lower levels as reported earlier. This study investigated the increase of arterial partial pressure of carbon dioxide between different flow rates of 100% oxygen in elective anesthetized and paralyzed surgical adults before intubation. METHODS After preoxygenation and standardized anesthesia induction with nondepolarizing neuromuscular blockade, all patients received 100% oxygen (via high-flow nasal oxygenation system or circuit of the anesthesia machine), and continuous jaw thrust/laryngoscopy was applied throughout the 15-min period. In this single-center noninferiority trial, 25 patients each, were randomized to five groups: (1) minimal flow: 0.25 l · min-1, endotracheal tube; (2) low flow: 2 l · min-1, continuous jaw thrust; (3) medium flow: 10 l · min-1, continuous jaw thrust; (4) high flow: 70 l · min-1, continuous jaw thrust; and (5) control: 70 l · min-1, continuous laryngoscopy. Immediately after anesthesia induction, the 15-min apnea period started with oxygen delivered according to the randomized flow rate. Serial arterial blood gas analyses were drawn every 2 min. The study was terminated if either oxygen saturation measured by pulse oximetry was less than 92%, transcutaneous carbon dioxide was greater than 100 mmHg, pH was less than 7.1, potassium level was greater than 6 mmol · l-1, or apnea time was 15 min. The primary outcome was the linear rate of mean increase of arterial carbon dioxide during the 15-min apnea period computed from linear regressions. RESULTS In total, 125 patients completed the study. Noninferiority with a predefined noninferiority margin of 0.3 mmHg · min-1 could be declared for all treatments with the following mean and 95% CI for the mean differences in the linear rate of arterial partial pressure of carbon dioxide with associated P values regarding noninferiority: high flow versus control, -0.0 mmHg · min-1 (-0.3, 0.3 mmHg · min-1, P = 0.030); medium flow versus control, -0.1 mmHg · min-1 (-0.4, 0.2 mmHg · min-1, P = 0.002); low flow versus control, -0.1 mmHg · min-1 (-0.4, 0.2 mmHg · min-1, P = 0.003); and minimal flow versus control, -0.1 mmHg · min-1 (-0.4, 0.2 mmHg · min-1, P = 0.004). CONCLUSIONS Widely differing flow rates of humidified 100% oxygen during apnea resulted in comparable increases of arterial partial pressure of carbon dioxide, which does not support an additional ventilatory effect of high-flow nasal oxygenation.
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Long-Term Outcomes of Radical Radiation Therapy with Hypoxia Modification with Biomarker Discovery for Stratification: 10-Year Update of the BCON (Bladder Carbogen Nicotinamide) Phase 3 Randomized Trial (ISRCTN45938399).
Song, YP, Mistry, H, Irlam, J, Valentine, H, Yang, L, Lane, B, West, C, Choudhury, A, Hoskin, PJ
International journal of radiation oncology, biology, physics. 2021;(5):1407-1415
Abstract
PURPOSE Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes. METHODS AND MATERIALS Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis. RESULTS We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08). CONCLUSIONS Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
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Randomised controlled trial to investigate the relationship between mild hypercapnia and cerebral oxygen saturation in patients undergoing major surgery.
Wong, C, Churilov, L, Cowie, D, Tan, CO, Hu, R, Tremewen, D, Pearce, B, Pillai, P, Karalapillai, D, Bellomo, R, et al
BMJ open. 2020;(2):e029159
Abstract
OBJECTIVES The effects of hypercapnia on regional cerebral oxygen saturation (rSO2) during surgery are unclear. We conducted a randomised controlled trial to investigate the relationship between mild hypercapnia and rSO2. We hypothesised that, compared with targeted normocapnia (TN), targeted mild hypercapnia (TMH) during major surgery would increase rSO2. DESIGN A prospective, randomised, controlled trial in adult participants undergoing elective major surgery. SETTING A single tertiary centre in Heidelberg, Victoria, Australia. PARTICIPANTS 40 participants were randomised to either a TMH or TN group (20 to each). INTERVENTIONS TMH (partial pressure of carbon dioxide in arterial blood, PaCO2, 45-55 mm Hg) or TN (PaCO2 35-40 mm Hg) was delivered via controlled ventilation throughout surgery. PRIMARY AND SECONDARY OUTCOME MEASURES The primary endpoint was the absolute difference between the two groups in percentage change in rSO2 from baseline to completion of surgery. Secondary endpoints included intraoperative pH, bicarbonate concentration, base excess, serum potassium concentration, incidence of postoperative delirium and length of stay (LOS) in hospital. RESULTS The absolute difference between the two groups in percentage change in rSO2 from the baseline to the completion of surgery was 19.0% higher in both hemispheres with TMH (p<0.001). On both sides, the percentage change in rSO2 was greater in the TMH group than the TN group throughout the duration of surgery. The difference between the groups became more noticeable over time. Furthermore, postoperative delirium was higher in the TN group (risk difference 0.3, 95% CI 0.1 to 0.5, p=0.02). LOS was similar between groups (5 days vs 5 days; p=0.99). CONCLUSION TMH was associated with a stable increase in rSO2 from the baseline, while TN was associated with a decrease in rSO2 in both hemispheres in patients undergoing major surgery. This resulted in a clear separation of percentage change in rSO2 from the baseline between TMH and TN over time. Our findings provide the rationale for larger studies on TMH during surgery. TRIAL REGISTRATION NUMBER The Australian New Zealand Clinical Trials Registry (ACTRN12616000320459).
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Dietary nitrate supplementation enhances cerebrovascular CO2 reactivity in a sex-specific manner.
Fan, JL, O'Donnell, T, Gray, CL, Croft, K, Noakes, AK, Koch, H, Tzeng, YC
Journal of applied physiology (Bethesda, Md. : 1985). 2019;(3):760-769
Abstract
Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day -1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% (P < 0.001) and lowered gain (d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment (d = 0.7, P = 0.043), while coherence was unaffected (P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men (d = 1.0, P = 0.014 vs. placebo), but had no effect in women (P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function.NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels' response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.
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The effect of L-rhamnose on intestinal transit time, short chain fatty acids and appetite regulation: a pilot human study using combined 13CO2/H2 breath tests.
Byrne, CS, Preston, T, Brignardello, J, Garcia-Perez, I, Holmes, E, Frost, GS, Morrison, DJ
Journal of breath research. 2018;(4):046006
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Abstract
BACKGROUND The appetite-regulating effects of non-digestible carbohydrates (NDC) have in part previously been attributed to their effects on intestinal transit rates as well as microbial production of short chain fatty acids (SCFA). Increased colonic production of the SCFA propionate has been shown to reduce energy intake and stimulate gut hormone secretion acutely in humans. OBJECTIVE We investigated the effect of the propiogenic NDC, L-rhamnose, on gastrointestinal transit times using a combined 13CO2/H2 breath test. We hypothesised that L-rhamnose would increase plasma propionate leading to a reduction in appetite, independent of changes in gastrointestinal transit times. DESIGN We used a dual 13C-octanoic acid/lactose 13C-ureide breath test combined with breath H2 to measure intestinal transit times following the consumption of 25 g d-1 L-rhamnose, compared with inulin and cellulose, in 10 healthy humans in a randomised cross-over design pilot study. Gastric emptying (GE) and oro-caecal transit times (OCTTs) were derived from the breath 13C data and compared with breath H2. Plasma SCFA and peptide YY (PYY) were also measured alongside subjective measures of appetite. RESULTS L-rhamnose significantly slowed GE rates (by 19.5 min) but there was no difference in OCTT between treatments. However, breath H2 indicated fermentation of L-rhamnose before it reached the caecum. OCTT was highly correlated with breath H2 for inulin but not for L-rhamnose or cellulose. L-rhamnose consumption significantly increased plasma propionate and PYY but did not significantly reduce subjective appetite measures. CONCLUSIONS The NDCs tested had a minimal effect on intestinal transit time. Our data suggest that L-rhamnose is partially fermented in the small intestine and that breath H2 reflects the site of gastrointestinal fermentation and is only a reliable marker of OCTT for certain NDCs (e.g. inulin). Future studies should focus on investigating the appetite-suppressing potential of L-rhamnose and verifying the findings in a larger cohort.
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An international collaboration studying the physiological and anatomical cerebral effects of carbon dioxide during head-down tilt bed rest: the SPACECOT study.
Marshall-Goebel, K, Mulder, E, Donoviel, D, Strangman, G, Suarez, JI, Venkatasubba Rao, C, Frings-Meuthen, P, Limper, U, Rittweger, J, Bershad, EM
Journal of applied physiology (Bethesda, Md. : 1985). 2017;(6):1398-1405
Abstract
Exposure to the microgravity environment results in various adaptive and maladaptive physiological changes in the human body, with notable ophthalmic abnormalities developing during 6-mo missions on the International Space Station (ISS). These findings have led to the hypothesis that the loss of gravity induces a cephalad fluid shift, decreased cerebral venous outflow, and increased intracranial pressure, which may be further exacerbated by increased ambient carbon dioxide (CO2) levels on the ISS. Here we describe the SPACECOT study (studying the physiological and anatomical cerebral effects of CO2 during head-down tilt), a randomized, double-blind crossover design study with two conditions: 29 h of 12° head-down tilt (HDT) with ambient air and 29 h of 12° HDT with 0.5% CO2 The internationally collaborative SPACECOT study utilized an innovative approach to study the effects of headward fluid shifting induced by 12° HDT and increased ambient CO2 as well as their interaction with a focus on cerebral and ocular anatomy and physiology. Here we provide an in-depth overview of this new approach including the subjects, study design, and implementation, as well as the standardization plan for nutritional intake, environmental parameters, and bed rest procedures.NEW & NOTEWORTHY A new approach for investigating the combined effects of cephalad fluid shifting and increased ambient carbon dioxide (CO2) is presented. This may be useful for studying the neuroophthalmic and cerebral effects of spaceflight where cephalad fluid shifts occur in an elevated CO2 environment.
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Dextran or Saline Can Replace Contrast for Intravascular Optical Coherence Tomography in Lower Extremity Arteries.
Kendrick, DE, Allemang, MT, Gosling, AF, Nagavalli, A, Kim, AH, Nishino, S, Parikh, SA, Bezerra, HG, Kashyap, VS
Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists. 2016;(5):723-30
Abstract
PURPOSE To examine the hypothesis that alternative flush media could be used for lower extremity optical coherence tomography (OCT) imaging in long lesions that would normally require excessive use of contrast. METHODS The OPTical Imaging Measurement of Intravascular Solution Efficacy (OPTIMISE) trial was a single-center, prospective study (ClinicalTrials.gov identifier NCT01743872) that enrolled 23 patients (mean age 68±11 years; 14 men) undergoing endovascular intervention involving the superficial femoral artery. Four flush media (heparinized saline, dextran, carbon dioxide, and contrast) were used in succession in random order for each image pullback. Quality was defined as ≥270° visualization of vessel wall layers from each axial image. Mean proportions (± standard deviation) of image quality for each flush medium were assessed using 1-way analysis of variance and are reported with the 95% confidence intervals (CI). RESULTS Four OCT catheters failed, leaving 19 patients who completed the OCT imaging protocol; from this cohort, 51 highest quality runs were selected for analysis. Average vessel diameter was 3.99±1.01 mm. OCT imaging allowed 10- to 15-μm resolution of the lumen border, with diminishing quality as vessel diameter increased. Plaque characterization revealed fibrotic lesions. Mean proportions of image quality were dextran 87.2%±12% (95% CI 0.81 to 0.94), heparinized saline 74.3%±24.8% (95% CI 0.66 to 0.93), contrast 70.1%±30.5% (95% CI 0.52 to 0.88), and carbon dioxide 10.0%±10.4% (95% CI 0.00 to 0.26). Dextran, saline, and contrast provided better quality than carbon dioxide (p<0.001). CONCLUSION OCT is feasible in peripheral vessels <5 mm in diameter. Dextran or saline flush media can allow lesion characterization, avoiding iodinated contrast. Carbon dioxide is inadequate for peripheral OCT imaging. Axial imaging may aid in enhancing durability of peripheral endovascular interventions.
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Effects of Twenty Days of the Ketogenic Diet on Metabolic and Respiratory Parameters in Healthy Subjects.
Rubini, A, Bosco, G, Lodi, A, Cenci, L, Parmagnani, A, Grimaldi, K, Zhongjin, Y, Paoli, A
Lung. 2015;(6):939-45
Abstract
PURPOSE The effects of the ketogenic diet (KD) on weight loss, metabolic, and respiratory parameters were investigated in healthy subjects. METHODS Thirty-two healthy subjects were randomized into two groups. The KD group followed a ketogenic diet for 20 days (KD t 0-t 20), then switched to a low-carbohydrate, no-ketogenic diet for 20 days (KD t 20-t 40), and finally was on a Mediterranean diet (MD) for 2 more months (KD t 40-t 2m). The MD group followed a MD for 20 days (MD t 0-t 20), then followed a MD of 1400 kcal over the next 20 days (MD t 20-t 40), and completed the study with the MD for 2 months (MD t 40-t 2m). Body weight, body fat, respiratory rate, and respiratory gas parameters (including respiratory exchange ratio (RER) and carbon dioxide end-tidal partial pressure (PETCO2), oxygen uptake (VO2), carbon dioxide production (VCO2), and resting energy expenditure (REE)) were measured at each point. RESULTS A significant decrease (p < 0.05) in RER was observed after 20 and 40 days in the KD group, but not in the MD group. In the KD group, significant reductions were observed for both carbon dioxide output and PETCO2, however, there was no significant change in VO2, VCO2, and REE. While both diets significantly decreased body fat mass, the KD diet overall proved to have a higher percentage of fat loss versus the MD diet. CONCLUSION The KD may significantly decrease carbon dioxide body stores, which may theoretically be beneficial for patients with increased carbon dioxide arterial partial pressure due to respiratory insufficiency or failure.
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Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial.
Thome, UH, Genzel-Boroviczeny, O, Bohnhorst, B, Schmid, M, Fuchs, H, Rohde, O, Avenarius, S, Topf, HG, Zimmermann, A, Faas, D, et al
The Lancet. Respiratory medicine. 2015;(7):534-43
Abstract
BACKGROUND Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING Deutsche Forschungsgemeinschaft.
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Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer.
Janssens, GO, Rademakers, SE, Terhaard, CH, Doornaert, PA, Bijl, HP, van den Ende, P, Chin, A, Takes, RP, de Bree, R, Hoogsteen, IJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;(5):1345-54
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Abstract
PURPOSE Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. EXPERIMENTAL DESIGN Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. RESULTS Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. CONCLUSION Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732).