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1.  Hypercapnia Improves Tissue Oxygenation in Morbidly Obese Surgical Patients 
Anesthesia and analgesia  2006;103(3):677-681.
Risk of wound infection is increased in morbidly obese surgical patients, in part because a major determinant of wound infection risk, tissue oxygenation, is marginal. Unlike in lean patients, supplemental inspired oxygen (FIO2) only slightly improves tissue oxygenation in obese patients. Mild hypercapnia improves tissue oxygenation in lean, but has not been evaluated in obese patients. We thus tested the hypothesis that mild hypercapnia markedly improves tissue oxygenation in morbidly obese patients given FIO2 80% during major abdominal surgery. Thirty obese patients (body mass index 61.5±17 kg/m2) scheduled for open gastric bypass were randomly assigned to normocapnia (n=15, end-tidal PCO2 35 mmHg) or hypercapnia (n=15, end-tidal PCO2 50 mmHg); FIO2 was 80%. Anesthetic management and other confounding factors were controlled. Tissue oxygen tension was measured subcutaneously at the upper arm using a polarographic probe in a silastic tonometer. Demographic characteristics, cardiovascular measurements, and PaO2 (222±48 versus 230±68 mmHg in normocapnic versus hypercapnic; mean±SD, P=0.705) were comparable in the groups. Tissue oxygen tension, however, was greater in hypercapnic than in normocapnic patients (78±31 versus 56±13 mmHg, P=0.029). Mild hypercapnia increased tissue oxygenation by an amount believed to be clinically important and could potentially reduce the risk of surgical wound infection in morbidly obese patients.
PMCID: PMC1555622  PMID: 16931680
obesity; hypercapnia; tissue oxygenation; and wound infection
2.  Cardiopulmonary effects of hypercapnia during controlled intermittent positive pressure ventilation in the horse. 
The cardiopulmonary effects of eucapnia (arterial CO2 tension [PaCO2] 40.4 +/- 2.9 mm Hg, mean +/- SD), mild hypercapnia (PaCO2, 59.1 +/- 3.5 mm Hg), moderate hypercapnia (PaCO2, 82.6 +/- 4.9 mm Hg), and severe hypercapnia (PaCO2, 110.3 +/- 12.2 mm Hg) were studied in 8 horses during isoflurane anesthesia with volume controlled intermittent positive pressure ventilation (IPPV) and neuromuscular blockade. The sequence of changes in PaCO2 was randomized. Mild hypercapnia produced bradycardia resulting in a significant (P < 0.05) decrease in cardiac index (CI) and oxygen delivery (DO2), while hemoglobin concentration (Hb), the hematocrit (Hct), systolic blood pressure (SBP), mean blood pressure (MBP), systemic vascular resistance (SVR), and venous admixture (QS/QT) increased significantly. Moderate hypercapnia resulted in a significant rise in CI, stroke index (SI), SBP, MBP, mean pulmonary artery pressure (PAP), Hct, Hb, arterial oxygen content (CaO2), mixed venous oxygen content (CvO2), and DO2, with heart rate (HR) staying below eucapnic levels. Severe hypercapnia resulted in a marked rise in HR, CI, SI, SBP, PAP, Hct, Hb, CaO2, CvO2, and DO2. Systemic vascular resistance was significantly decreased, while MBP levels were not different from those during moderate hypercapnia. No cardiac arrhythmias were recorded with any of the ranges of PaCO2. Norepinephrine levels increased progressively with each increase in PaCO2, whereas plasma cortisol levels remained unchanged. It was concluded that hypercapnia in isoflurane-anesthetized horses elicits a biphasic cardiopulmonary response, with mild hypercapnia producing a fall in CI and DO2 despite an increase in MBP, while moderate and severe hypercapnia produce an augmentation of the cardiopulmonary performance and DO2.
PMCID: PMC1263768  PMID: 8521355
3.  Impact of phenylephrine administration on cerebral tissue oxygen saturation and blood volume is modulated by carbon dioxide in anaesthetized patients† 
BJA: British Journal of Anaesthesia  2012;108(5):815-822.
Multiple studies have shown that cerebral tissue oxygen saturation () is decreased after phenylephrine treatment. We hypothesized that the negative impact of phenylephrine administration on is affected by arterial blood carbon dioxide partial pressure () because CO2 is a powerful modulator of cerebrovascular tone.
In 14 anaesthetized healthy patients, i.v. phenylephrine bolus was administered to increase the mean arterial pressure ∼20–30% during hypocapnia, normocapnia, and hypercapnia. and cerebral blood volume (CBV) were measured using frequency domain near-infrared spectroscopy, a quantitative technology. Data collection occurred before and after each treatment.
Phenylephrine caused a significant decrease in during hypocapnia [=−3.4 (1.5)%, P<0.001], normocapnia [=−2.4 (1.5)%, P<0.001], and hypercapnia [=−1.4 (1.5)%, P<0.01]. Decreases in were significantly different between hypocapnia, normocapnia, and hypercapnia (P<0.001). Phenylephrine also caused a significant decrease in CBV during hypocapnia (P<0.01), but not during normocapnia or hypercapnia.
The negative impact of phenylephrine treatment on and CBV is intensified during hypocapnia while blunted during hypercapnia.
PMCID: PMC3325051  PMID: 22391890
carbon dioxide; cerebral blood volume; cerebral tissue oxygen saturation; modulation; phenylephrine
4.  Hyperlactatemia during cardiopulmonary bypass: determinants and impact on postoperative outcome 
Critical Care  2006;10(6):R167.
Hyperlactatemia during cardiopulmonary bypass is relatively frequent and is associated with an increased postoperative morbidity. The aim of this study was to determine which perfusion-related factors may be responsible for hyperlactatemia, with specific respect to hemodilution and oxygen delivery, and to verify the clinical impact of hyperlactatemia during cardiopulmonary bypass in terms of postoperative morbidity and mortality rate.
Five hundred consecutive patients undergoing cardiac surgery with cardiopulmonary bypass were admitted to this prospective observational study. During cardiopulmonary bypass, serial arterial blood gas analyses with blood lactate and glucose determinations were obtained. Hyperlactatemia was defined as a peak arterial blood lactate concentration exceeding 3 mmol/l. Pre- and intraoperative factors were tested for independent association with the peak arterial lactate concentration and hyperlactatemia. The postoperative outcome of patients with or without hyperlactatemia was compared.
Factors independently associated with hyperlactatemia were the preoperative serum creatinine value, the presence of active endocarditis, the cardiopulmonary bypass duration, the lowest oxygen delivery during cardiopulmonary bypass, and the peak blood glucose level. Once corrected for other explanatory variables, hyperlactatemia during cardiopulmonary bypass remained significantly associated with an increased morbidity, related mainly to a postoperative low cardiac output syndrome, but not to mortality.
Hyperlactatemia during cardiopulmonary bypass appears to be related mainly to a condition of insufficient oxygen delivery (type A hyperlactatemia). During cardiopulmonary bypass, a careful coupling of pump flow and arterial oxygen content therefore seems mandatory to guarantee a sufficient oxygen supply to the peripheral tissues.
PMCID: PMC1794481  PMID: 17134504
5.  Association between initial prescribed minute ventilation and post-resuscitation partial pressure of arterial carbon dioxide in patients with post-cardiac arrest syndrome 
Post-cardiac arrest hypocapnia/hypercapnia have been associated with poor neurological outcome. However, the impact of arterial carbon dioxide (CO2) derangements during the immediate post-resuscitation period following cardiac arrest remains uncertain. We sought to test the correlation between prescribed minute ventilation and post-resuscitation partial pressure of CO2 (PaCO2), and to test the association between early PaCO2 and neurological outcome.
We retrospectively analyzed a prospectively compiled single-center cardiac arrest registry. We included adult (age ≥ 18 years) patients who experienced a non-traumatic cardiac arrest and required mechanical ventilation. We analyzed initial post-resuscitation ventilator settings and initial arterial blood gas analysis (ABG) after initiation of post-resuscitation ventilator settings. We calculated prescribed minute ventilation:
for each patient. We then used Pearson’s correlation to test the correlations between prescribed MV and PaCO2. We also determined whether patients had normocapnia (PaCO2 between 30 and 50 mmHg) on initial ABG and tested the association between normocapnia and good neurological function (Cerebral Performance Category 1 or 2) at hospital discharge using logistic regression analyses.
Seventy-five patients were included. The majority of patients were in-hospital arrests (85%). Pulseless electrical activity/asystole was the initial rhythm in 75% of patients. The median (IQR) TV, RR, and MV were 7 (7 to 8) mL/kg, 14 (14 to 16) breaths/minute, and 106 (91 to 125) mL/kg/min, respectively. Hypocapnia, normocapnia, and hypercapnia were found in 15%, 62%, and 23% of patients, respectively. Good neurological function occurred in 32% of all patients, and 18%, 43%, and 12% of patients with hypocapnia, normocapnia, and hypercapnia respectively. We found prescribed MV had only a weak correlation with initial PaCO2, R = -0.40 (P < 0.001). Normocapnia was associated with good neurological function, odds ratio 4.44 (95% CI 1.33 to 14.85).
We found initial prescribed MV had only a weak correlation with subsequent PaCO2 and that early Normocapnia was associated with good neurological outcome. These data provide rationale for future research to determine the impact of PaCO2 management during mechanical ventilation in post-cardiac arrest patients.
PMCID: PMC3973966  PMID: 24602367
Cardiac arrest; Heart arrest; Cardiopulmonary resuscitation; Resuscitation; Anoxic brain injury; Shock; Hypocapnia; Hypercapnia; Minute ventilation
6.  A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial 
Trials  2015;16:135.
Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial.
The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months.
The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12612000690853.
PMCID: PMC4393877  PMID: 25872502
cardiac arrest; hypercapnia; intensive care; normocapnia; randomized trial; resuscitation
7.  Effects of intra-operative end-tidal carbon dioxide levels on the rates of post-operative complications in adults undergoing general anesthesia for percutaneous nephrolithotomy: A clinical trial 
A retrospective study has shown lesser days of hospital stay in patients with increased levels of intra-operative end-tidal carbon dioxide (ETCO2). It is probable that hypercapnia may exert its beneficial effects on patients’ outcome through optimization of global hemodynamic and tissue oxygenation, leading to a lower rate of post-operative complications. This study was designed to test the hypothesis that higher values of intra-operative ETCO2 decrease the rate of post-operative complications.
Materials and Methods:
In this randomized, double-blind clinical trial, 78 adult patients scheduled for percutaneous nephrolithotomy (PCNL) were prospectively enrolled and randomly divided into three groups. ETCO2 was set and maintained throughout the procedure at 31-33, 37-39 and 43-45 mmHg in the hypocapnia, normocapnia and hypercapnia groups, respectively. The rates of post-operative complications were compared among the three groups.
Seventy-five patients completed the study (52 male and 23 female). Ten (38.5%), four (16%) and two (8.3%) patients developed post-operative vomiting in the hypocapnia, normocapnia and hypercapnia groups, respectively (P = 0.025). The nausea score was significantly lower in the hypercapnic group compared with the other groups (3.9 ± 1.8, 3.2 ± 2.1 and 1.3 ± 1.8 in the hypocapnia, normocapnia and hypercapnia groups, respectively; P = 0.000). Time to return of spontaneous respiration and awakening were significantly decreased in the hypercapnia group compared with the other groups (P < 0.01).
Mild intra-operative hypercapnia has a protecting effect against the development of post-operative nausea and vomiting and decreases the duration of emergence and recovery from general anesthesia.
PMCID: PMC3988596  PMID: 24761392
Carbon dioxide; hypercapnia; hypocapnia; nausea and vomiting; post-operative complications
8.  The effect of hypercapnia on static cerebral autoregulation 
Physiological Reports  2014;2(6):e12059.
Hypercapnia impairs cerebrovascular control during rapid changes in blood pressure (BP); however, data concerning the effect of hypercapnia on steady state, nonpharmacological increases in BP is scarce. We recruited fifteen healthy volunteers (mean ± SD: age, 28 ± 6 years; body mass, 77 ± 12 kg) to assess the effect of hypercapnia on cerebrovascular control during steady‐state elevations in mean arterial BP (MAP), induced via lower body positive pressure (LBPP). Following 20 min of supine rest, participants completed 5 min of eucapnic 20 and 40 mm Hg LBPP (order randomized) followed by 5 min of hypercapnia (5% CO2 in air) with and without LBPP (order randomized), and each stage was separated by ≥5 min to allow for recovery. Middle cerebral artery blood velocity (MCAv), BP, partial pressure of end‐tidal carbon dioxide (PETCO2) and heart rate were recorded and presented as the change from the preceding baseline. No difference in MCAv was apparent between eupcapnic baseline and LBPPs (grouped mean 65 ± 11 cm·s−1, all P >0.05), despite the increased MAP with LBPP (Δ6 ± 5 and Δ8 ± 3 mm Hg for 20 and 40 mm Hg, respectively, both P <0.001 vs. baseline). Conversely, MCAv during the hypercapnic +40 mm Hg stage (Δ31 ± 13 cm·s−1) was greater than hypercapnia alone (Δ25 ± 11 cm·s−1, P =0.026), due to an increased MAP (Δ14 ± 7 mm Hg, P <0.001 vs. hypercapnia alone and P =0.026 vs. hypercapnia +20 mm Hg). As cardiac output and PETCO2 were similar across all hypercapnic stages (all P >0.05), our findings indicate that hypercapnia impairs static autoregulation, such that higher blood pressures are translated into the cerebral circulation.
This experiment investigated the effects of Hypercapnia on static cerebral autoregulation in healthy humans using lower body positive pressure mediated increases in MAP. It was found that nonpharmacological increases in MAP are translated to the cerebral circulation during hypercapnia.
PMCID: PMC4208638  PMID: 24973333
Cerebral blood flow; hypercapnia; lower body positive pressure; static cerebral autoregulation
9.  Influence of CO2 on neurovascular coupling: interaction with dynamic cerebral autoregulation and cerebrovascular reactivity 
Physiological Reports  2014;2(3):e00280.
PaCO2 affects cerebral blood flow (CBF) and its regulatory mechanisms, but the interaction between neurovascular coupling (NVC), cerebral autoregulation (CA), and cerebrovascular reactivity to CO2 (CVR), in response to hypercapnia, is not known. Recordings of cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end‐tidal CO2 (EtCO2) were performed in 18 subjects during normocapnia and 5% CO2 inhalation while performing a passive motor paradigm. Together with BP and EtCO2, a gate signal to represent the effect of stimulation was used as input to a multivariate autoregressive‐moving average model to calculate their separate effects on CBFv. Hypercapnia led to a depression of dynamic CA at rest and during stimulation in both hemispheres (P <0.02) as well as impairment of the NVC response, particularly in the ipsilateral hemisphere (P <0.01). Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The CBFv step responses to each individual input (BP, EtCO2, stimulation) allowed identification of the influences of hypercapnia and neuromotor stimulation on CA, CVR, and NVC, which have not been previously described, and also confirmed the depressing effects of hypercapnia on CA and NVC. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation. Dynamic multivariate modeling can identify the complex interplay between different CBF regulatory mechanisms and should be recommended for studies involving similar interactions, such as the effects of exercise or posture on cerebral hemodynamics.
The influence of hypercapnia on dynamic cerebral autoregulation (CA), CO2 vasoreactivity (CVR), and neurovascular coupling (NVC) was described based on a single recording during motor stimulation coupled to a new multivariate modeling approach. Hypercapnia led to a depression of CA at rest and during stimulation in both hemispheres as well as impairment of the NVC response. Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation.
PMCID: PMC4002257  PMID: 24760531
Carbon dioxide; cerebral hemodynamics; cerebrovascular reactivity; dynamic cerebral autoregulation; neurovascular coupling
10.  Supplemental Oxygen and Carbon Dioxide Each Increase Subcutaneous and Intestinal Intramural Oxygenation 
Anesthesia and analgesia  2004;99(1):207-211.
Oxidative killing by neutrophils, a primary defense against surgical pathogens, is directly related to tissue oxygenation. We tested the hypothesis that supplemental inspired oxygen or mild hypercapnia (end-tidal PCO2 of 50 mmHg) improves intestinal oxygenation. Pigs (25±2.5 kg) were used in two studies in random order: 1) Oxygen Study — 30% vs. 100% inspired oxygen concentration at an end-tidal PCO2 of 40 mmHg, and 2) Carbon Dioxide Study — end-tidal PCO2 of 30 mmHg vs. 50 mmHg with 30% oxygen. Within each study, treatment order was randomized. Treatments were maintained for 1.5 hours; measurements were averaged over the final hour. A tonometer inserted in the subcutaneous tissue of the left upper foreleg measured subcutaneous oxygen tension. Tonometers inserted into the intestinal wall measured intestinal intramural oxygen tension from the small and large intestines. 100% oxygen administration doubled subcutaneous oxygen partial pressure (PO2) (57±10 to 107±48 mmHg, P=0.006) and large intestine intramural PO2 (53±14 to 118±72 mmHg, P=0.014); intramural PO2increased 40% in the small intestine (37±10 to 52±25 mmHg, P=0.004). An end-tidal PCO2 of 50 mmHg increased large intestinal PO2 approximately 16% (49±10 to 57±12 mmHg, P=0.039), while intramural PO2 increased by 45% in the small intestine (31±12 to 44±16 mmHg, P=0.002). Supplemental oxygen and mild hypercapnia each increased subcutaneous and intramural tissue PO2, with supplemental oxygen being most effective.
PMCID: PMC1360187  PMID: 15281531
Oxygen: Intramural, Subcutaneous Intestinal; Ventilation: Increased Oxygen, Carbon Dioxide
11.  The effect of sodium salicylate on cerebral blood flow and metabolism. 
British Journal of Pharmacology  1980;68(3):407-411.
1 The effect of intravenous sodium salicylate on cerebral oxygen consumption and cerebral blood flow and its response to hypercapnia was measured by the 133Xenon intracarotid injection technique in ten baboons. 2 After an initial peak, the plasma salicylate level maintained a stable value for 2 h of 1 mmol/l with 50 mg/kg sodium salicylate and 2.5 mmol/l with 200 mg/kg sodium salicylate. 3 Sodium salicylate (50 mg/kg) produced no change in baseline cerebral blood flow (CBF) or cerebral oxygen consumption (CMRO2) but the CBF response to hypercapnia was reduced by 41% during the first hour. During the second hour after salicylate administration, CMRO2 increased by 26%, CBF at normocapnia increased by 31% and the CBF response to hypercapnia was 67% of the baseline value. 4 Sodium salicylate (200 mg/kg) increased CMRO2 by 65%. There was no significant change in CBF at normocapnia or hypercapnia. 5 These results confirm that inhibitors of prostaglandin synthesis, which can cross the blood brain barrier in sufficient quantity, reduce the response of the cerebral circulation to hypercapnia. The difficulties in interpreting changes in the CBF CO2 response in the presence of increases in CMRO2 are discussed. It is suggested that the respiratory stimulation seen in salicylate intoxication is the result of a central metabolic stimulation.
PMCID: PMC2044200  PMID: 6820297
12.  Very Low Tidal Volume Ventilation with Associated Hypercapnia - Effects on Lung Injury in a Model for Acute Respiratory Distress Syndrome 
PLoS ONE  2011;6(8):e23816.
Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome.
Methodology/Principal Findings
In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8–10 ml/kg/PaCO2 = 40 mm Hg; Group 2: tidal volume = 4–5 ml/kg/PaCO2 = 80 mm Hg; Group 3: tidal volume = 3–4 ml/kg/PaCO2 = 120 mm Hg; Group 4: tidal volume = 2–3 ml/kg/PaCO2 = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO2 were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4–5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy.
Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4–5 ml/kg/PaCO2 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained.
PMCID: PMC3158784  PMID: 21886825
13.  Effect of artificial respiratory volume on the cardiovascular responses to an alpha 1- and an alpha 2-adrenoceptor agonist in the air-ventilated pithed rat. 
British Journal of Pharmacology  1988;93(4):781-790.
1. The effect of varying artificial respiratory volume (at a fixed rate of 54 min-1) on cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in control pithed rats or during pressor responses to either the alpha 1-adrenoceptor agonist phenylephrine or the alpha 2-agonist xylazine. Phenylephrine was investigated in the presence of propranolol (3 mg kg-1). The rats were pithed under halothane anaesthesia. 2. A respiratory volume of 15 ml kg-1 produced modest hypercapnia (PaCO2 = 47 mmHg), hypoxia (PaO2 = 60 mmHg) and acidosis (pH = 7.35) relative to control animals respired at 20 ml kg-1 (PaCO2 = 32 mmHg; PaO2 = 77 mmHg; pH = 7.47). In rats respired at 15 ml kg-1, total peripheral resistance was lower, and cardiac output greater (due to increased stroke volume), than in the controls. Lowering respiratory volume reduced distribution of cardiac output to the kidneys, increased it to the large intestine and also increased blood flow through the gastrointestinal tract, skin and spleen. A respiratory volume of 30 ml kg-1 gave mild hypocapnia (PaCO2 = 19 mmHg), hyperoxia (PaO2 = 101 mmHg) and alkalosis (pH = 7.59) compared to 20 ml kg-1 but had no effect on cardiac output distribution or organ blood flow although heart rate was 29% greater at 30 ml kg-1. 3. Xylazine (500 micrograms bolus followed by 100 micrograms min-1 infusion) at all three respiratory volumes gave well-sustained mean pressor responses of 62-64 mmHg by increasing both total peripheral resistance and cardiac output (resulting from increased stroke volume). It increased the proportion of cardiac output passing to the liver, reduced that going to the spleen and gastrointestinal tract and increased cardiac, renal and hepatosplanchnic blood flows. 4. The secondary, relatively sustained, pressor effect of phenylephrine (5 micrograms bolus followed by 0.4 micrograms min-1 infusion, i.v.) varied at the 3 respiratory volumes with mean values from 32 to 53 mmHg. This response was due to both increased total peripheral resistance and cardiac output (resulting from greater stroke volumes and/or heart rates). Phenylephrine increased the proportion of cardiac output passing to the gastrointestinal tract, heart, kidneys and hepatosplanchnic bed and increased cardiac, hepatosplanchnic, renal and gastrointestinal blood flows. 5. Respiratory volume had no effect on the cardiovascular effects of xylazine. However, respiratory volume modified the effects of phenylephrine on heart rate and changed the relative contributions of stroke volume and heart rate to the increased cardiac output.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC1853908  PMID: 2898957
14.  Efficacy and safety of a low-flow veno-venous carbon dioxide removal device: results of an experimental study in adult sheep 
Critical Care  2006;10(5):R151.
Extracorporeal lung assist, an extreme resource in patients with acute respiratory failure (ARF), is expanding its indications since knowledge about ventilator-induced lung injury has increased and protective ventilation has become the standard in ARF.
A prospective study on seven adult sheep was conducted to quantify carbon dioxide (CO2) removal and evaluate the safety of an extracorporeal membrane gas exchanger placed in a veno-venous pump-driven bypass. Animals were anaesthetised, intubated, ventilated in order to reach hypercapnia, and then connected to the CO2 removal device. Five animals were treated for three hours, one for nine hours, and one for 12 hours. At the end of the experiment, general anaesthesia was discontinued and animals were extubated. All of them survived.
No significant haemodynamic variations occurred during the experiment. Maintaining an extracorporeal blood flow of 300 ml/minute (4.5% to 5.3% of the mean cardiac output), a constant removal of arterial CO2, with an average reduction of 17% to 22%, was observed. Arterial partial pressure of carbon dioxide (PaCO2) returned to baseline after treatment discontinuation. No adverse events were observed.
We obtained a significant reduction of PaCO2 using low blood flow rates, if compared with other techniques. Percutaneous venous access, simplicity of circuit, minimal anticoagulation requirements, blood flow rate, and haemodynamic impact of this device are more similar to renal replacement therapy than to common extracorporeal respiratory assistance, making it feasible not only in just a few dedicated centres but in a large number of intensive care units as well.
PMCID: PMC1751056  PMID: 17069660
15.  Respiratory sinus arrhythmia in dogs. Effects of phasic afferents and chemostimulation. 
Journal of Clinical Investigation  1991;87(5):1621-1627.
We examined the hypothesis that respiratory sinus arrhythmia (RSA) is primarily a central phenomenon and thus that RSA is directly correlated with respiratory controller output. RSA was measured in nine anesthetized dogs, first during spontaneous breathing (SB) and then during constant flow ventilation (CFV), a technique whereby phasic chest wall movements and thoracic pressure swings are eliminated. Measurements of the heart rate and of the moving time averaged (MTA) phrenic neurogram during these two ventilatory modes were made during progressive hypercapnia and progressive hypoxia. RSA divided by the MTA phrenic amplitude (RSAa) showed a power-law relationship with both arterial carbon dioxide partial pressure (PaCO2) and oxygen saturation (SaO2), but with different exponents for different conditions. However, the power-law relation between RSAa and respiratory frequency had an exponent indistinguishable from -2 whether hypoxia or hypercapnia was the stimulus for increased respiratory drive, and during both CFV and spontaneous breathing (-1.9 +/- 0.4, hypoxia, SB; -1.8 +/- 0.7, hypoxia, CFV; -2.1 +/- 0.8, hypercapnia, SB; -1.9 +/- 0.7, hypercapnia, CFV). We conclude that respiratory sinus arrhythmia is centrally mediated and directly related to respiratory drive, and that changes in blood gases and phasic afferent signals affect RSA primarily by influencing respiratory drive.
PMCID: PMC295245  PMID: 1902491
16.  Effects of rac-albuterol on arterial blood gases in patients with stable hypercapnic chronic obstructive pulmonary disease 
Many patients with chronic obstructive pulmonary disease (COPD) are treated with high dose β2-adrenoceptor agonists, which can increase ventilation/perfusion mismatching, and tremor and cardiac output, thereby increasing oxygen uptake and carbon dioxide output (VCO2). Patients with severe COPD and hypercapnia may be unable to increase ventilation in response to increased VCO2, in which case arterial carbon dioxide tension (PaCO2) may rise. Our aim was to determine whether high dose nebulized rac-albuterol could increase PaCO2 in patients with COPD, limited bronchodilator reversibilty and hypercapnia.
We compared 10 mg and 400 µg rac-albuterol, given in two doses 1 h apart on nonconsecutive days, in a double-blind randomized crossover study in 14 patients with severe COPD. PaCO2, arterial oxygen tension (PaO2) and heart rate were measured over 120 min and change from baseline was plotted against time to obtain an area under the curve.
Mean PaCO2 fell slightly over 120 min, with no difference between treatments (0.03 kPa h−1 (95% confidence interval 0.02, 0.04)) and only three subjects had an increase in PaCO2 after high dose rac-albuterol. High dose rac-albuterol caused a greater fall in PaO2 [0.1 kPa h−1 (95% confidence interval 0, 0.2)] and increase in heart rate than the low dose, although the differences were small.
Under stable conditions most subjects with severe COPD and hypercapnia will have a fall in PaCO2 and PaO2 following 10 mg rac-albuterol, suggesting that they maintain capacity to respond to any increase in VCO2 and prevent a rise in PaCO2.
PMCID: PMC1885093  PMID: 16842389
albuterol; COPD; hypercapnia; salbutamol
17.  Variations in Alveolar Partial Pressure for Carbon Dioxide and Oxygen Have Additive Not Synergistic Acute Effects on Human Pulmonary Vasoconstriction 
PLoS ONE  2013;8(7):e67886.
The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (Paco2) and oxygen (Pao2) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of Paco2 (+6, +1, −4 and −9 mmHg, relative to baseline) with four levels of Pao2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both Paco2 and the calculated haemoglobin oxygen desaturation (1-So2). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, Paco2 and So2. No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p>0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output.
PMCID: PMC3729950  PMID: 23935847
18.  Managing Hypercapnia in Patients with Severe ARDS and Low Respiratory System Compliance: The Role of Esophageal Pressure Monitoring—A Case Cohort Study 
BioMed Research International  2015;2015:385042.
Purpose. Patients with severe acute respiratory distress syndrome (ARDS) and hypercapnia present a formidable treatment challenge. We examined the use of esophageal balloon for assessment of transpulmonary pressures to guide mechanical ventilation for successful management of severe hypercapnia. Materials and Methods. Patients with severe ARDS and hypercapnia were studied. Esophageal balloon was inserted and mechanical ventilation was guided by assessment of transpulmonary pressures. Positive end expiratory pressure (PEEP) and inspiratory driving pressures were adjusted with the aim of achieving tidal volume of 6 to 8 mL/kg based on ideal body weight (IBW), while not exceeding end inspiratory transpulmonary (EITP) pressure of 25 cm H2O. Results. Six patients with severe ARDS and hypercapnia were studied. Mean PaCO2 on enrollment was 108.33 ± 25.65 mmHg. One hour after adjustment of PEEP and inspiratory driving pressure guided by transpulmonary pressure, PaCO2 decreased to 64.5 ± 16.89 mmHg (P < 0.01). Tidal volume was 3.96 ± 0.92 mL/kg IBW before and increased to 7.07 ± 1.21 mL/kg IBW after intervention (P < 0.01). EITP pressure before intervention was low with a mean of 13.68 ± 8.69 cm H2O and remained low at 16.76 ± 4.76 cm H2O (P = 0.18) after intervention. Adjustment of PEEP and inspiratory driving pressures did not worsen oxygenation and did not affect cardiac output significantly. Conclusion. The use of esophageal balloon as a guide to mechanical ventilation was able to treat severe hypercapnia in ARDS patients.
PMCID: PMC4324110  PMID: 25695069
19.  Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain 
Physiological Reports  2014;2(8):e12127.
Mechanisms by which Pco2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in Paco2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated Pco2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP‐dependent dilator, isoproterenol, and cGMP‐dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60%. Glibenclamide treatment during hypercapnia constricted arterioles ~35%. The level of hypercapnia, Paco2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to Paco2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.
Mechanisms by which Pco2 controls vascular tone remain uncertain. We hypothesize KATP and KCa channel activation contributes to the neonatal cerebrovascular dilation in response to increases in Paco2. Presented data support this hypothesis.
PMCID: PMC4246596  PMID: 25168876
Cerebrovascular circulation; in vivo cranial window; newborn pig; potassium channels
20.  Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care 
Critical Care  2000;4(5):302-308.
The respiratory effects of dexmedetomidine were retrospectively examined in 33 postsurgical patients involved in a randomised, placebo-controlled trial after extubation in the intensive care unit (ICU). Morphine requirements were reduced by over 50% in patients receiving dexmedetomidine. There were no differences in respiratory rates, oxygen saturations, arterial pH and arterial partial carbon dioxide tension (PaCO2) between the groups. Interestingly the arterial partial oxygen tension (PaO2) : fractional inspired oxygen (FIO2) ratios were statistically significantly higher in the dexmedetomidine group. Dexmedetomidine provides important postsurgical analgesia and appears to have no clinically important adverse effects on respiration in the surgical patient who requires intensive care.
The α2-agonist dexmedetomidine is a new class of sedative drug that is being investigated for use in ICU settings. It is an effective agent for the management of sedation and analgesia after cardiac, general, orthopaedic, head and neck, oncological and vascular surgery in the ICU [1]. Cardiovascular stability was demonstrated, with significant reductions in rate-pressure product during sedation and over the extubation period.
Dexmedetomidine possesses several properties that may additionally benefit those critically ill patients who require sedation. In spontaneously breathing volunteers, intravenous dexmedetomidine caused marked sedation with only mild reductions in resting ventilation at higher doses [2]. Dexmedetomidine reduces the haemodynamic response to intubation and extubation [3,4,5] and attenuates the stress response to surgery [6], as a result of the α2-mediated reduction in sympathetic tone. Therefore, it should be possible to continue sedation with dexmedetomidine over the stressful extubation period without concerns over respiratory depression, while ensuring that haemodynamic stability is preserved.
The present study is a retrospective analysis of the respiratory response to dexmedetomidine in 33 postsurgical patients (who were involved in a randomized, double-blind, placebo-controlled trial [1]) after extubation in the ICU.
Patients who participated in the present study were admitted after surgery to our general or cardiothoracic ICUs, and were expected to receive at least 6 h of postsurgical sedation and artificial ventilation.
On arrival in the ICU after surgery, patients were randomized to receive either dexmedetomidine or placebo (normal saline) with rescue sedation and analgesia being provided, only if clinically needed, with midazolam and morphine boluses, respectively. Sedation was titrated to maintain a Ramsay Sedation Score [7] of 3 or greater while the patients were intubated, and infusions of study drug were continued for a maximum of 6 h after extubation to achieve a Ramsay Sedation Score of 2 or greater.
The patients were intubated and ventilated with oxygen-enriched air to attain acceptable arterial blood gases, and extubation occurred when clinically indicated. All patients received supplemental oxygen after extubation, which was delivered by a fixed performance device. Assessment of pain was by direct communication with the patient.
Results are expressed as mean ± standard deviation unless otherwise stated. Patient characteristics, operative details and morphine usage were analyzed using the Mann-Whitney U-test. Statistical differences for respiratory measurements between the two groups were determined using analysis of variance for repeated measures, with the Bonferroni test for post hoc comparisons.
Of the 40 patients who participated in the study, seven patients could not be included in the analysis of respiratory function because they did not receive a study drug infusion after extubation. Consequently, data from 33 patients are used in the analysis of respiratory function; 16 received dexmedetomidine and 17 placebo. Inadequate arterial blood gas analysis was available in five patients (two from the dexmedetomidine group, and three from the placebo group). There were no significant differences in patient characteristics and operative details between the groups.
Requirements for morphine were reduced by more than 50% in patients receiving dexmedetomidine when compared with placebo after extubation (0.003 ± 0.004 vs 0.008 ± 0.006 mg/kg per h; P= 0.040).
There were no statistically significant differences between placebo and dexmedetomidine for oxygen saturations measured by pulse oximetry (P= 0.26), respiratory rate (P= 0.16; Fig. 1), arterial pH (P= 0.77) and PaCO2 (P= 0.75; Fig. 2) for the 6 h after extubation.
The dexmedetomidine group showed significantly higher PaO2: FIO2 ratios throughout the 6-h intubation (P= 0.036) and extubation (P= 0.037) periods (Fig. 3). There were no adverse respiratory events seen in either the dexmedetomidine or placebo group.
Respiratory rate for the 6-h periods before and after extubation. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaCO2 (PCO2) for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaO2 : FIO2 ratio for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
Lack of respiratory depression in patients sedated with α2-adrenoceptor agonists was first reported by Maxwell [8] in a study investigating the respiratory effects of clonidine. However, more recent data suggests that clonidine may cause mild respiratory depression in humans [9], and α2-adrenoceptor agonists are well known to produce profound intraoperative hypoxaemia in sheep [10,11]. The effects of dexmedetomidine on other ventilation parameters also appear to be species specific [12].
Belleville et al [2] investigated the ventilatory effects of a 2-min intravenous infusion of dexmedetomidine on human volunteers. According to those investigators, minute ventilation and arterial PaCO2 were mildly decreased and increased, respectively. There was a rightward shift and depression of the hypercapnic response with infusions of 1.0 and 2.0 μg/kg.
Previous studies that investigated the respiratory effects of dexmedetomidine have only been performed in healthy human volunteers, who have received either single intramuscular injections or short (= 10 min) intravenous infusions of dexmedetomidine. It is therefore reassuring that no deleterious clinical effects on respiration and gas exchange were seen in the patients we studied, who were receiving long-term infusions. However, there are important limitations to the present results. No dose/response curve for dexmedetomidine can be formulated from the data, and further investigation is probably ethically difficult to achieve in the spontaneously ventilating intensive care patient. We also have no data on the ventilatory responses to hypercapnia and hypoxia, which would also be difficult to examine practically and ethically. The placebo group received more than twice as much morphine as patients receiving dexmedetomidine infusions after extubation, but there were no differences in respiratory rate or PaCO2 between the groups. We can not therefore determine from this study whether dexmedetomidine has any benefits over morphine from a respiratory perspective.
There were no differences in oxygen saturations between the groups because the administered oxygen concentration was adjusted to maintain satisfactory gas exchange. Interestingly, however, there were statistically significant higher PaO2 : FIO2 ratios in the dexmedetomidine group. This ratio allows for the variation in administered oxygen to patients during the study period, and gives some clinical indication of alveolar gas exchange. However, this variable was not a primary outcome variable for the present study, and may represent a type 1 error, although post hoc analysis reveals that the data have 80% power to detect a significant difference (α value 0.05). Further studies are obviously required.
Sedation continued over the extubation period, has been shown to reduce haemodynamic disturbances and myocardial ischaemia [13]. We have previously shown [1] that dexmedetomidine provides cardiovascular stability, with a reduction in rate-pressure product over the extubation period. A sedative agent that has analgesic properties, minimal effects on respiration and offers ischaemia protection would have enormous potential in the ICU. Dexmedetomidine may fulfill all of these roles, but at present we can only conclude that dexmedetomidine has no deleterious clinical effects on respiration when used in doses that are sufficient to provide adequate sedation and effective analgesia in the surgical population requiring intensive care.
PMCID: PMC29047  PMID: 11056756
α2-Adrenoceptor agonist; analgesia; dexmedetomidine; intensive care; postoperative; respiratory; sedation
21.  The influence of carbon dioxide on brain activity and metabolism in conscious humans 
A better understanding of carbon dioxide (CO2) effect on brain activity may have a profound impact on clinical studies using CO2 manipulation to assess cerebrovascular reserve and on the use of hypercapnia as a means to calibrate functional magnetic resonance imaging (fMRI) signal. This study investigates how an increase in blood CO2, via inhalation of 5% CO2, may alter brain activity in humans. Dynamic measurement of brain metabolism revealed that mild hypercapnia resulted in a suppression of cerebral metabolic rate of oxygen (CMRO2) by 13.4%±2.3% (N=14) and, furthermore, the CMRO2 change was proportional to the subject's end-tidal CO2 (Et-CO2) change. When using functional connectivity MRI (fcMRI) to assess the changes in resting-state neural activity, it was found that hypercapnia resulted in a reduction in all fcMRI indices assessed including cluster volume, cross-correlation coefficient, and amplitude of the fcMRI signal in the default-mode network (DMN). The extent of the reduction was more pronounced than similar indices obtained in visual-evoked fMRI, suggesting a selective suppression effect on resting-state neural activity. Scalp electroencephalogram (EEG) studies comparing hypercapnia with normocapnia conditions showed a relative increase in low frequency power in the EEG spectra, suggesting that the brain is entering a low arousal state on CO2 inhalation.
PMCID: PMC3049465  PMID: 20842164
carbon dioxide; cerebral metabolic rate of oxygen; electroencephalogram; functional connectivity MRI; hypercapnia
22.  Impact of Intermittent Apnea on Myocardial Tissue Oxygenation—A Study Using Oxygenation-Sensitive Cardiovascular Magnetic Resonance 
PLoS ONE  2013;8(1):e53282.
Carbon dioxide (CO2) is a recognized vasodilator of myocardial blood vessels that leads to changes in myocardial oxygenation through the recruitment of the coronary flow reserve. Yet, it is unknown whether changes of carbon dioxide induced by breathing maneuvers can be used to modify coronary blood flow and thus myocardial oxygenation. Oxygenation-sensitive cardiovascular magnetic resonance (CMR) using the blood oxygen level-dependent (BOLD) effect allows for non-invasive monitoring of changes of myocardial tissue oxygenation. We hypothesized that mild hypercapnia induced by long breath-holds leads to changes in myocardial oxygenation that can be detected by oxygenation-sensitive CMR.
Methods and Results
In nine anaesthetized and ventilated pigs, 60s breath-holds were induced. Left ventricular myocardial and blood pool oxygenation changes, as monitored by oxygenation-sensitive CMR using a T2*-weighted steady-state-free-precession (SSFP) sequence at 1.5T, were compared to changes of blood gas levels obtained immediately prior to and after the breath-hold. Long breath-holds resulted in an increase of paCO2, accompanied by a decrease of paO2 and pH. There was a significant decrease of blood pressure, while heart rate did not change. A decrease in the left ventricular blood pool oxygenation was observed, which was similar to drop in SaO2. Oxygenation in the myocardial tissue however, was maintained throughout the period. Changes in myocardial oxygenation were strongly correlated with the change in paCO2 during the breath-hold (r = 0.90, p = 0.010).
Despite a drop in blood oxygen levels, myocardial oxygenation is maintained throughout long breath-holds and is linearly correlated with the parallel increase of arterial CO2, a known coronary vasodilator. Breathing maneuvers in combination with oxygenation-sensitive CMR may be useful as a diagnostic test for coronary artery function.
PMCID: PMC3536756  PMID: 23301055
23.  Assessment of Myocardial Reactivity to Controlled Hypercapnia with Free-breathing T2-prepared Cardiac Blood Oxygen Level–Dependent MR Imaging 
Radiology  2014;272(2):397-406.
Free-breathing T2-prepared myocardial blood oxygen level–dependent MR responses under hypercapnia of 10 mm Hg and adenosine are not different.
To examine whether controlled and tolerable levels of hypercapnia may be an alternative to adenosine, a routinely used coronary vasodilator, in healthy human subjects and animals.
Materials and Methods
Human studies were approved by the institutional review board and were HIPAA compliant. Eighteen subjects had end-tidal partial pressure of carbon dioxide (PetCO2) increased by 10 mm Hg, and myocardial perfusion was monitored with myocardial blood oxygen level–dependent (BOLD) magnetic resonance (MR) imaging. Animal studies were approved by the institutional animal care and use committee. Anesthetized canines with (n = 7) and without (n = 7) induced stenosis of the left anterior descending artery (LAD) underwent vasodilator challenges with hypercapnia and adenosine. LAD coronary blood flow velocity and free-breathing myocardial BOLD MR responses were measured at each intervention. Appropriate statistical tests were performed to evaluate measured quantitative changes in all parameters of interest in response to changes in partial pressure of carbon dioxide.
Changes in myocardial BOLD MR signal were equivalent to reported changes with adenosine (11.2% ± 10.6 [hypercapnia, 10 mm Hg] vs 12% ± 12.3 [adenosine]; P = .75). In intact canines, there was a sigmoidal relationship between BOLD MR response and PetCO2 with most of the response occurring over a 10 mm Hg span. BOLD MR (17% ± 14 [hypercapnia] vs 14% ± 24 [adenosine]; P = .80) and coronary blood flow velocity (21% ± 16 [hypercapnia] vs 26% ± 27 [adenosine]; P > .99) responses were similar to that of adenosine infusion. BOLD MR signal changes in canines with LAD stenosis during hypercapnia and adenosine infusion were not different (1% ± 4 [hypercapnia] vs 6% ± 4 [adenosine]; P = .12).
Free-breathing T2-prepared myocardial BOLD MR imaging showed that hypercapnia of 10 mm Hg may provide a cardiac hyperemic stimulus similar to adenosine.
© RSNA, 2014
Online supplemental material is available for this article.
PMCID: PMC4263621  PMID: 24749715
24.  Rapid magnetic resonance measurement of global cerebral metabolic rate of oxygen consumption in humans during rest and hypercapnia 
The effect of hypercapnia on cerebral metabolic rate of oxygen consumption (CMRO2) has been a subject of intensive investigation and debate. Most applications of hypercapnia are based on the assumption that a mild increase in partial pressure of carbon dioxide has negligible effect on cerebral metabolism. In this study, we sought to further investigate the vascular and metabolic effects of hypercapnia by simultaneously measuring global venous oxygen saturation (SvO2) and total cerebral blood flow (tCBF), with a temporal resolution of 30 seconds using magnetic resonance susceptometry and phase-contrast techniques in 10 healthy awake adults. While significant increases in SvO2 and tCBF were observed during hypercapnia (P<0.005), no change in CMRO2 was noted (P>0.05). Additionally, fractional changes in tCBF and end-tidal carbon dioxide (R2=0.72, P<0.005), as well as baseline SvO2 and tCBF (R2=0.72, P<0.005), were found to be correlated. The data also suggested a correlation between cerebral vascular reactivity (CVR) and baseline tCBF (R2=0.44, P=0.052). A CVR value of 6.1%±1.6%/mm Hg was determined using a linear-fit model. Additionally, an average undershoot of 6.7%±4% and 17.1%±7% was observed in SvO2 and tCBF upon recovery from hypercapnia in six subjects.
PMCID: PMC3137470  PMID: 21505481
carotid artery; cerebral blood flow measurement; cerebral hemodynamics; energy metabolism; MRI
25.  Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction 
Respiratory Research  2012;13(1):7.
Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined.
We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability.
In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W.
Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent.
PMCID: PMC3306743  PMID: 22292558
hypoxia; hypercapnia; acidosis; nitric oxide; hypoxic pulmonary vasoconstriction

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