Physiological Targets for Orthostatic Hypotension: Improving Nonpharmacological Interventions in Patients with Orthostatic Cerebral Hypoperfusion.

Orthostatic hypotension (OH) is a form of orthostatic intolerance (OI) and a key physiological indicator of autonomic dysfunction that is associated with an increased risk of major cerebrocardiovascular events. Symptoms of cerebral hypoperfusion have been reported in patients with OH, which worsens symptoms and increases the risk of syncope. Since pharmacological interventions increase blood pressure (BP) independent of posture and do not restore normal baroreflex control, nonpharmacological treatments are considered the foundation of OH management. While reductions in cerebral blood flow velocity (CBFv) during orthostatic stress are associated with a decrease in end-tidal CO2 (EtCO2) and hypocapnia in patients with OI, their contribution to the severity of OH is not well understood. These measures have been physiological targets in a wide variety of biofeedback interventions. This study explored the relationship between cardiovascular autonomic control, EtCO2 and cerebral hypoperfusion in patients (N = 72) referred for OI. Patients with systolic OH were more likely to be male, older, demonstrate reduced adrenal and vagal baroreflex sensitivity, and reduced cardiovagal control during head-up tilt (HUT) than patients without systolic OH. Greater reduction in CBFv during HUT was associated with a larger reduction in ETCO2 and systolic BP during HUT. While deficits in cardiovascular autonomic control played a more important role in systolic OH, reduced EtCO2 was a major contributor to orthostatic cerebral hypoperfusion. These findings suggest that biofeedback treatments targeting both the autonomic nervous system and EtCO2 should be part of nonpharmacological interventions complementing the standard of care in OH patients with symptoms of cerebral hypoperfusion.

Hypocapnia in early hours of life is associated with brain injury in moderate to severe neonatal encephalopathy.

OBJECTIVE: To evaluate the association between hypocapnia within the first 24 h of life and brain injury assessed by a detailed MRI scoring system in infants receiving therapeutic hypothermia (TH) for neonatal encephalopathy (NE) stratified by the stage of NE. STUDY DESIGN: This retrospective cohort study included infants who received TH for mild to severe NE. RESULTS: 188 infants were included in the study with 48% having mild and 52% moderate-severe NE. Infants with moderate-severe NE spent more time in hypocapnia (PCO2 ≤ 35 mmHg) and presented with more severe brain injury on MRI compared to mild cases. The MRI injury score increased by 6% for each extra hour spent in hypocapnic range in infants with moderate-severe NE. There was no association between hypocapnia and injury scores in mild cases. CONCLUSION: In infants with moderate-severe NE, the hours spent in hypocapnia was an independent predictor of brain injury.

Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO2: the HENRIC feasibility and safety trial.

BACKGROUND: There is an association between hypocapnia and adverse neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our aim was to test the safety and feasibility of 5% CO2 and 95% air inhalation to correct hypocapnia in mechanically ventilated infants with NE undergoing therapeutic hypothermia. METHODS: Ten infants were assigned to this open-label, single-center trial. The gas mixture of 5% CO2 and 95% air was administered through patient circuits if the temperature-corrected PCO2 ≤40 mm Hg. The CO2 inhalation was continued for 12 h or was stopped earlier if the base deficit (BD) level decreased <5 mmol/L. Follow-up was performed using Bayley Scales of Infant Development II. RESULTS: The patients spent a median 95.1% (range 44.6-98.5%) of time in the desired PCO2 range (40-60 mm Hg) during the inhalation. All PCO2 values were >40 mm Hg, the lower value of the target range. Regression modeling revealed that BD and lactate had a tendency to decrease during the intervention (by 0.61 and 0.55 mmol/L/h, respectively), whereas pH remained stable. The rate of moderate disabilities and normal outcome was 50%. CONCLUSIONS: Our results suggest that inhaled 5% CO2 administration is a feasible and safe intervention for correcting hypocapnia.

Mediators of Change in Capnometry Guided Respiratory Intervention for Panic Disorder.

Capnometry guided respiratory interventions have shown promising results in the treatment of panic disorder, but mechanisms of change are not yet well-understood. The current study examined changes in end-tidal carbon dioxide (ETCO2), anxiety sensitivity, and perceived control as mediators of panic symptom change. Sixty-nine adults with panic disorder received 4 weeks of respiratory training, and panic symptom severity and potential mediators were assessed at Pre-treatment, Mid-treatment, Post-treatment, 2-month follow-up, and 12-month follow-up. Multilevel mediation analyses showed that changes in perceived control significantly mediated changes in panic disorder severity and that for individuals who were hypocapnic at pre-treatment, ETCO2 was a significant mediator of symptom outcome. Findings provide further evidence that changes in perceived control, and improvements in respiratory dysregulation for hypocapnic individuals specifically, underlie symptom improvement from capnometry guided respiratory intervention for panic disorder.

Targeting two different levels of both arterial carbon dioxide and arterial oxygen after cardiac arrest and resuscitation: a randomised pilot trial.

PURPOSE: We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury. METHODS: Using a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5-4.7 kPa) or high-normal (5.8-6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10-15 kPa) or moderate hyperoxia (PaO2 20-25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months. RESULTS: In total 120 patients were included in the analyses. There was a clear separation in PaCO2 (p < 0.001) and PaO2 (p < 0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9-28.3 µg/l) in the low-normal PaCO2 group and 22.5 µg/l (14.2-34.9 µg/l) in the high-normal PaCO2 group, p = 0.400; and 22.3 µg/l (14.8-27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2-34.9 µg/l) in the moderate hyperoxia group, p = 0.594). High-normal PaCO2 and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes. CONCLUSIONS: Both high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected. REGISTRATION: ClinicalTrials.gov, NCT02698917. Registered on January 26, 2016.

Carbon dioxide therapy in hypocapnic respiratory failure.

Oxygen therapy, usually administered by a facemask or nasal cannulae, is the current default treatment of respiratory failure. Since respiration entails intake of oxygen and release of carbon dioxide from tissues as waste product, the notion of administering carbon dioxide in respiratory failure appears counter-intuitive. However, carbon dioxide stimulates the chemosensitive area of the medulla, known as the central respiratory chemoreceptor, which activates the respiratory groups of neurones in the brainstem and stimulates inspiration thereby initiating oxygen intake during normal breathing. This vital initiation of normal breathing is via a reduction in the pH of the cerebrospinal fluid and the medullary interstitial fluid. We hypothesise that in cases of type I respiratory failure in which the PaCO2 is low, administration of carbon dioxide by inhalation would stimulate the respiratory groups of brainstem neurones and facilitate breathing, which would be of therapeutic value. Preliminary clinical evidence in favour of this hypothesis is presented and we recommend that a formal randomised study be carried out.

Hypo- and hypercapnia predict mortality in oxygen-dependent chronic obstructive pulmonary disease: a population-based prospective study.

BACKGROUND: The prognostic role of the arterial blood gas tension of carbon dioxide (PaCO2) in severe Chronic Obstructive Pulmonary Disease (COPD) remains unknown. The aim of this study was to estimate the association between PaCO2 and mortality in oxygen-dependent COPD. METHODS: National prospective study of patients starting long-term oxygen therapy (LTOT) for COPD in Sweden between October 1, 2005 and June 30, 2009, with all-cause mortality as endpoint. The association between PaCO2 while breathing air, PaCO2 (air), and mortality was estimated using Cox regression adjusted for age, sex, arterial blood gas tension of oxygen (PaO2), World Health Organization performance status, body mass index, comorbidity, and medications. RESULTS: Of 2,249 patients included, 1,129 (50%) died during a median 1.1 years (IQR 0.6-2.0 years) of observation. No patient was lost to follow-up. PaCO2 (air) independently predicted adjusted mortality (p < 0.001). The association with mortality was U-shaped, with the lowest mortality at approximately PaCO2 (air) 6.5 kPa and increased mortality at PaCO2 (air) below 5.0 kPa and above 7.0 kPa. CONCLUSION: In oxygen-dependent COPD, PaCO2 (air) is an independent prognostic factor with a U-shaped association with mortality.

Normalizing CO2 in chronic hyperventilation by means of a novel breathing mask: a pilot study.

INTRODUCTION: Chronic idiopathic hyperventilation (CIH) is a form of dysfunctional breathing that has proven hard to treat effectively. OBJECTIVES: To perform a preliminary test of the hypothesis that by periodically inducing normocapnia over several weeks, it would be possible to raise the normal resting level of CO2 and achieve a reduction of symptoms. METHODS: Six CIH patients were treated 2 h a day for 4 weeks with a novel breathing mask. The mask was used to induce normocapnia in these chronically hypocapnic patients. Capillary blood gases and acid/base parameters [capillary CO2 tension (PcapCO2 ), pH, and standard base excess (SBE)] were measured at baseline and once each week at least 3 h after mask use, as well as spirometric values, breath-holding tolerance and hyperventilation symptoms as per the Nijmegen Questionnaire (NQ). RESULTS: The mask treatment resulted in a significant increase of resting PcapCO2 (+0.45 kPa, P = 0.028), a moderate increase in SBE (+1.4 mEq/L, P = 0.035) and a small reduction in daily symptoms (-3.8 NQ units, P = 0.046). The effect was most pronounced in the first 2 weeks of treatment. CONCLUSION: By inducing normocapnia with the breathing mask 2 h a day for 4 weeks, the normal resting CO2 and acid/base levels in chronically hyperventilating patients were partially corrected, and symptoms were reduced.

Effectiveness of Adaptive Servo Ventilation in the treatment of hypocapnic central sleep apnea of various etiologies.

BACKGROUND: Central sleep apnea (CSA) occurs in clinical situations that induce hypocapnia and respiratory instability during sleep. This is true, not only in heart failure patients, but also in patients suffering from neurological diseases and idiopathic CSA. Adaptive Servo Ventilation (ASV) is frequently prescribed in France for the treatment of CSA, but only a few studies have evaluated ASV treatment with regards to long term effectiveness and compliance. METHODS: Retrospective chart review in two French centers of the outcome of 74 CSA patients treated by ASV with a mean follow up on ASV of 36±18 months. RESULTS: Thirty-three of the 74 patients suffered from CSA related to heart failure (HF), whereas the 41 others exhibited CSA mainly associated with neurological disorders or idiopathic CSA. Mean ASV compliance was 5.2±2.6 and 5.9±2.9h per night in cardiac failure and non-cardiac failure patients, respectively. All patients significantly improved their apnea+hypopnea index (from 47.4±19.8 to 6.9±9.3/h [p<0.001]) and mean nocturnal SaO(2) (from 92.1±2.6% to 93.6±3.2% [p<0.001]). The Epworth sleepiness scale score was reduced from 10.2±5.2 to 6.5±3.9 (p<0.01) in compliant patients but not in non-compliant patients (less than 3h per night). Moreover, compliant cardiac failure patients demonstrated a significant improvement in their NYHA score [p<0.05]. Lastly, ASV significantly reduced chronic hyperventilation as assessed by blood gases. CONCLUSION: Our findings suggest that ASV is well tolerated and effective for most patients with hypocapnic central sleep apnea and chronic hyperventilation.

Effects of GV20 acupuncture on cerebral blood flow velocity of middle cerebral artery and anterior cerebral artery territories, and CO2 reactivity during hypocapnia in normal subjects.

OBJECTIVES: Acupuncture has been gaining popularity among practitioners of modern medicine as an alternative and complementary treatment. However, the mechanism of its therapeutic effect still remains uncertain. The present study chose the GV20 acupoint to evaluate acupoint effectiveness, hypothesizing that its stimulation induces cerebrovascular responses. DESIGN AND SETTING: The effects of GV20 acupuncture treatment on middle cerebral artery (MCA) and anterior cerebral artery (ACA) blood flow velocities, and CO(2) reactivity during hypocapnia were evaluated in 10 healthy male subjects (mean age 25.6 ± 0.8 years). Measurements were done at rest and during hypocapnia, and were repeated four times each at different cerebral artery territories with an interval of 1 week. MCA and ACA blood flow velocities were measured with a transcranial Doppler flowmeter. Blood flow velocity was corrected to 40 mm Hg of end-tidal CO(2) partial pressure (P(ETCO2)), and was expressed as CV40. CO(2) reactivity was measured as percent change in mean blood flow velocity/mm Hg P(ETCO2). RESULTS: Mean MCA and ACA blood flow velocities at rest, CV40, and CO(2) reactivity during hypocapnia increased significantly after GV20 acupuncture treatment, whereas mean arterial blood pressure and pulse rate at rest did not change significantly. The increases in MCA and ACA blood flow velocity were associated with improved CO(2) reactivity after GV20 acupuncture treatment. CONCLUSIONS: The data suggest that GV20 acupuncture treatment increases cerebral blood flow. The results of this small-scale study provide preliminary evidence for acupuncture effectiveness.

Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: To evaluate the association between early hypocarbia and 18- to 22-month outcome among neonates with hypoxic-ischemic encephalopathy. STUDY DESIGN: Data from the National Institute of Child Health and Human Development Neonatal Research Network randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy were used for this secondary observational study. Infants (n = 204) had multiple blood gases recorded from birth to 12 hours of study intervention (hypothermia versus intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18 to 22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO(2) and cumulative exposure to PCO(2) <35 mm Hg. The relationship between cumulative PCO(2) <35 mm Hg (calculated as the difference between 35 mm Hg and the sampled PCO(2) multiplied by the duration of time spent <35 mm Hg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), and time to spontaneous respiration and ventilator days; results were expressed as odds ratios and 95% confidence intervals. Alternative models of CO(2) concentration were explored to account for fluctuations in CO(2). RESULTS: Both minimum PCO(2) and cumulative PCO(2) <35 mm Hg were associated with poor outcome (P < .05). Moreover, death/disability increased with greater cumulative exposure to PCO(2) <35 mm Hg. CONCLUSIONS: Hypocarbia is associated with poor outcome after hypoxic-ischemic encephalopathy.

Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies.

Sustained or spontaneous hyperventilation has been associated with a variety of physical symptoms and has been linked to a number of organic illnesses and mental disorders. Theories of panic disorder hold that hyperventilation either produces feared symptoms of hypocapnia or protects against feared suffocation symptoms of hypercapnia. Although the evidence for both theories is inconclusive, findings from observational, experimental, and therapeutic studies suggest an important role of low carbon dioxide (CO2) levels in this disorder. Similarly, hypocapnia and associated hyperpnia are linked to bronchoconstriction, symptom exacerbation, and lower quality of life in patients with asthma. Raising CO2 levels by means of therapeutic capnometry has proven beneficial effects in both disorders, and the reversing of hyperventilation has emerged as a potent mediator for reductions in panic symptom severity and treatment success.

Treatment of positive airway pressure treatment-associated respiratory instability with enhanced expiratory rebreathing space (EERS).

STUDY OBJECTIVES: Hypocapnia is an important mediator of sleep-dependent respiratory instability. Positive pressure-associated ventilatory control instability results in poor control of sleep apnea and persistent sleep fragmentation. We tested the adjunctive efficacy of low volumes of dead space (enhanced expiratory rebreathing space [EERS]) using a non-vented mask to minimize sleep hypocapnia. DESIGN: Retrospective chart review. SETTING: American Academy of Sleep Medicine accredited sleep center and laboratory. INTERVENTION: Enhanced expiratory rebreathing space MEASUREMENTS AND RESULTS: 204 patients diagnosed with continuous positive pressure (CPAP)-refractory sleep apnea between 1/1/04 and 7/1/06 were included in this retrospective review. All patients had in-lab attended polysomnography for diagnosis, conventional CPAP titration, and further assessments of added EERS. EERS volume was titrated to control of disease, which was typically obtained when end-tidal (ET) CO2 during sleep was 1-2 mm Hg above wake eupneic CO2 levels. The clinic records were reviewed for clinical outcomes. Poor laboratory response to, and initial clinical abandonment of CPAP, was very common (89.2%) in this group of patients, who as a group demonstrated mild resting wake hypocapnia (ETCO2 = 38.1 ± 3.1 mm Hg). Minimizing sleep hypocapnia by adding 100-150 mL EERS (mean ETCO2) at optimal therapy 38.6 ± 2.9 mm Hg) markedly improved polysomnographic control of sleep apnea, without inducing tachypnea or tachycardia. Follow-up (range 30-1872 days) showed improved clinical tolerance, compliance, and sustained clinical improvement. Leak and sleep fragmentation modified clinical outcomes. CONCLUSIONS: EERS is a potentially useful adjunctive therapy for positive pressure-associated respiratory instability and salvage of some CPAP treatment failures.

Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure.

RATIONALE: There is increasing evidence of increased ventilatory instability in patients with obstructive sleep apnea (OSA), but previous investigations have not studied whether the hypocapnic apneic threshold is altered in this group. OBJECTIVES: To compare the apneic threshold, CO2 reserve, and controller gain between subjects with and without OSA matched for age, sex, and body mass index. METHODS: Hypocapnia was induced via nasal mechanical ventilation for 3 minutes. Cessation of mechanical ventilation resulted in hypocapnic central hypopnea or apnea depending upon the magnitude of the hypocapnia. The apnea threshold (Pet(CO2)-AT) was defined as the measured Pet(CO2) at which the apnea closest to the last hypopnea occurred. The CO2 reserve was defined as the change in Pet(CO2) between eupneic Pet(CO2) and Pet(CO2)-AT. Controller gain was defined as the ratio of change in Ve between control and hypopnea or apnea to the DeltaPet(CO2). MEASUREMENTS AND MAIN RESULTS: Eleven pairs of subjects were studied. There was no difference in the Pet(CO2)-AT between the two groups. However, the CO2 reserve was smaller in the subjects with OSA (2.2 +/- 0.6 mm Hg) compared with the control subjects (4.5 +/- 1.4 mm Hg; P < 0.001). The controller gain was increased in the subjects with OSA (3.7 +/- 1.3 L/min/mm Hg) compared with the control subjects (1.6 +/- 0.5 L/min/mm Hg; P < 0.001). Controller gain decreased and CO2 reserve increased in seven subjects restudied after using continuous positive airway pressure for 1 month. CONCLUSIONS: Ventilatory instability is increased in subjects with OSA and is reversible with the use of continuous positive airway pressure.

Breathing evaluation and retraining in manual therapy.

Patients with back and neck pain commonly seek body work yet there are some who do not experience full recovery with the typical tool kit of manual therapy, education and exercise, suggesting the need for additional clinical approaches. Epidemiological literature linking back pain with breathing difficulties suggests one possibility. Altered motor control associated with back and neck pain appears to negatively impact breathing mechanics, which may have negative consequences on respiratory chemistry. Changes in respiratory chemistry can have profound effects on body system function. Altered breathing has been recognized for many years as a potential source of a wide variety of unexplained symptoms. There has been controversy around accurate diagnosis with symptoms and questionnaires often being the only methods used. Capnography, which is routinely used in critical care settings, offers an objective measure of respiratory chemistry providing physiological data on which to base a diagnosis of poor breathing. Capnography can also be used as biofeedback to guide breathing retraining.

Prehospital hypocapnia and poor outcome after severe traumatic brain injury.

BACKGROUND: The Brain Trauma Foundation (BTF) Guidelines for prehospital management of traumatic brain injury (TBI) recommend a goal end-tidal carbon dioxide of 30 mm Hg to 35 mm Hg in patients without signs of herniation. METHODS: We examined prehospital concordance with BTF Guidelines, selected demographic and physiologic variables and outcomes for 100 consecutive admissions to a well-established Level I regional trauma center. All patients had blunt TBI with Glasgow Coma Score < or = 8 without signs of herniation. All were transported by helicopter by flight paramedics experienced with BTF Guidelines and the continuous wave form capnometer. Patients resumed spontaneous ventilation after intubation. RESULTS: Concordance (prehospital end-tidal carbon dioxide > 29 mm Hg) was achieved in 65 of 100 cases. Mortality was 29% (19 of 65) among those in whom guideline levels were achieved prehospital and 46% (16 of 35) in those in whom guideline levels were not achieved prehospital (odds ratio, 0.49; p = 0.10). The "achieved" group was younger (p = 0.02), with higher calculated probability of survival (p = 0.01). Intracranial pressure was maintained under intensive care within acceptable limits in the hospital in both groups but was significantly higher in the "not achieved" group (p = 0.05). CONCLUSIONS: Our data, though not statistically significant, suggest that patients who are harder to keep within the guidelines in the field are more likely to die, because of more severe TBI or complication by other factors such as age or injury severity. Whether increased awareness of this phenomenon can improve outcomes is unknown but suggests an approach to future education and research.