- Email: [email protected]
Periodic Breathing With No Heart Beat
However, accumulating experience, including this case report, suggests that clinicians should consider ivacaftor treatment of all patients with CF and a gating mutation. Whether all such patients will respond well to ivacaftor remains to be demonstrated, and significant barriers to off-label use of this costly new drug likely will arise.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245. 2. Reboul MP, Bieth E, Fayon M, et al. Splice mutation 1811 1 1.6kbA.G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients. J Med Genet. 2002;39(11):e73. 3. Boucher RC. Cystic fibrosis: a disease of vulnerability to airway surface dehydration. Trends Mol Med. 2007;13(6): 231-240. 4. Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18): 1663-1672. 5. Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. 6. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44): 18825-18830. 7. Yarlagadda S, Zhang W, Penmatsa H, et al. A young Hispanic with c.1646G.A mutation exhibits severe cystic fibrosis lung disease: is ivacaftor an option for therapy? Am J Respir Crit Care Med. 2012;186(7):694-696. 8. Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013;143(1): 14-18.
Periodic Breathing With No Heart Beat Stephen Bartsch, MD; and Philippe Haouzi, MD
A protocol was originally designed to study breathing control during and following cardiac arrest in humans, taking advantage of the period of pulseless ventricular fibrillation (PVF) produced while testing a newly implanted cardioverter-defibrillator device. A patient aged in his 60s with New York Heart Association class III heart failure (HF) (left ventricular ejection fraction of 25%) who was originally part of this study displayed permanent periodic breathing (PB) and was
then excluded from the final data analysis; his response is presented in this report. The 8- to 9-s PVF was incidentally produced during the ascending phase of a PB cycle, followed by another 12-s recovery period of low BP. PVF and its recovery had no effect on PB characteristics (period or amplitude). This occurred despite a profound change in PACO2, cerebral blood flow, and perfusion of the carotid bodies. It is concluded that PB in patients with HF could be produced by primary oscillations originating from the central pattern generator. CHEST 2013; 144(4):1378–1380 Abbreviations: CB 5 carotid body; HF 5 heart failure; ICD 5 implantable cardioverter-defibrillator device; PB 5 periodic breathing; PVF 5 pulseless ventricular fibrillation
T
he mechanisms believed to cause periodic breathing (PB) in patients with heart failure (HF) include enhanced gain of the carotid bodies (CBs),1 increased circulatory time,2 periodic variations in cerebral blood flow-induced brainstem changes in pH,3 or primary oscillating mechanisms within the central pattern generator for breathing.4 Although many of these mechanisms can be reproduced experimentally and can lead to breathing instability, there is still a vivid debate on the frame of reference to be used to understand PB in patients with HF.3 We had the opportunity to record the breathing pattern of a male patient aged in his 60s with New York Heart Association class III HF (left ventricular ejection fraction of 25%) who displayed long periods of PB (with cycles lasting from 40-50 s). This patient, who had no history of stroke or other neurologic deficit traditionally associated with PB, was originally part of an institutional review board-approved study on the control of breathing during cardiac arrest. This patient was excluded from that study because of the lack of stable baseline ventilation. The procedure consisted of a subcutaneous placement of an implantable cardioverter-defibrillator device (ICD) (Intrinsic DR ICD generator; Medtronic, Inc) for standard clinical indications under IV conscious sedation with propofol (diisopropylphenol). Inspiratory and expiratory flows were measured via a low-dead-space face mask connected to a pneumotachograph (Fleisch Pneumotachograph # 2; Phipps & Bird, Inc). Expired CO2 was continuously measured, and end-tidal Pco2 (Paco2) was determined using a fast infrared CO2 analyzer (VacuMed). The ventilatory variables were recorded (PowerLab; ADInstruments) along with BP (Finapres Medical Systems BV) and the ECG during Manuscript received December 8, 2012; revision accepted March 12, 2013. Affiliations: From the Division of Pulmonary and Critical Care Medicine, Penn State University College of Medicine, Penn State Hershey Medical Center, Hershey, PA. Part of this article has been presented in abstract form (Bartsch S, Haouzi P. Am J Respir Crit Care Med. 2012;185:A2053). Correspondence to: Philippe Haouzi, MD, Penn State University College of Medicine, Penn State Hershey Medical Center, Division of Pulmonary and Critical Care Medicine, 500 University Dr, Hershey, PA 17033; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2950
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Selected Reports
the entire procedure of ICD placement. In accordance with standard clinical protocols, the ICD was tested at the end of the procedure by the induction of pulseless ventricular fibrillation (PVF) (high-frequency burst pacing, 50 Hz, 8 V), allowing for the appropriate discharge of the device to restore sinus rhythm. The episode of PFV occurred during the ascending phase of a PB cycle (Fig 1) leading to a dramatic drop in BP (Fig 1) for 8 to 9 s. This period of asystole was followed by a period of low BP for another 12 s after defibrillation. At the very onset of a cardiac arrest, systemic peripheral blood flow is certainly not instantaneously null, as pressures between the arterial compartment (in which the pressure drops) and the venous system (wherein pressure increases) will slowly equilibrate until the mean filling pressure is reached, creating some peripheral blood flow; however, as soon as the cardiac pump stops, systemic blood flow is expected to reach a level difficult to reconcile with any significant form of gas transport. Therefore, blood flow must have been severely reduced for . 20 s after the onset of PFV. Despite the expected reduction in both pulmonary and
systemic blood flow, PVF had no visible effect on the periodicity or the amplitude of this or the subsequent PB cycles ( Fig 1 ). Yet, the reduction in blood flow to the carotid chemoreceptors during the period of PVF should have erased the intrabreath oscillations in Paco2-induced CB stimulation.5 In addition, this reduction in systemic blood flow should have also reset any PB pattern, which would have been caused by cerebral blood flow oscillations and/or circulatory delay.3 Upon the slow return to normal circulatory conditions, the blood leaving the pulmonary circulation is expected to have been transiently hypocapnic and hyperoxic, as a result of the persistent ventilatory activity with no (then low) pulmonary blood flow.6 Indeed, as the entire period of PVF occurred during the ascending phase of a PB cycle, the rise in end-tidal Pco2 that occurred typically before the peak of the breathing oscillations was abolished following defibrillation. As shown in Figure 1, this led to a reduction in alveolar Pco2 by 7 mm Hg during the PB cycle, when PVF was triggered, compared with other BP cycles. Perhaps more importantly, the prolonged reduction in systemic venous return and arterial supply during the
Figure 1. A, Recording obtained during implanted cardioverter-defibrillator device (ICD) replacement. The following signals are displayed: end-tidal CO2 fraction, respiratory flow, tidal volume, continuous noninvasive BP, and ECG. The entire period of pulseless ventricular fibrillation (PVF) PVF (between the two vertical arrows) incidentally occurred during the ascending phase of a PB cycle. Note that ICD discharge caused a very brief muscle contraction of the chest wall with a transient artifact on the airflow, BP, and ECG signals. The periods of induced PVF and its recovery following the firing of the implantable cardiac defibrillator lasted for 20 s or so, whereas the temporal profile, periodicity, and amplitude of PB were not affected (see also C). B, Magnification of the period of cardiac arrest and defibrillation showing end-tidal CO2, BP, respiratory flow, and mean BP signals. Clearly, BP, and, thus, blood flow, remained low beyond the period of PVF (ie, for ⱖ 10 s after defibrillation). C, End-tidal CO2 and respiratory flow signals of the PB cycle during which PVF (black line) was produced, superimposed on the subsequent PB cycle (red line). Note that despite a difference in Paco2 by approximately 7 mm Hg and the additional delay in circulatory time during the loss and return of spontaneous circulation, PB pattern was not affected except for a transient alteration of two breaths, which occurred during defibrillation. *Artifact on the Finapres BP signal. Feco2 5 end-tidal CO2 fraction; 5 respiratory flow; Vt 5 tidal volume. journal.publications.chestnet.org
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period of PVF and its subsequent slow recovery must have resulted in a continuous, rather than oscillatory, stimulation of the central chemoreceptors as tissue CO2 accumulates and local acidosis develops. This continuous stimulation should have produced a distortion in PB oscillations, which we did not observe. Therefore, the present observation is difficult to reconcile with the theories assuming that PB can be produced and maintained via a prolonged circulatory delay, change in the gain of the CB, or the consequences of periodic fluctuations in cerebral blood flow. This intriguing observation of unchanged PB during and following cardiac arrest suggests that a primary oscillating central mechanism could be the main controller of breath cycles in PB, at least in some patients with HF.5
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Topor ZL, Vasilakos K, Younes M, Remmers JE. Model based analysis of sleep disordered breathing in congestive heart failure. Respir Physiol Neurobiol. 2007;155(1):82-92. 2. Crowell JW, Guyton AC, Moore JW. Basic oscillating mechanism of Cheyne-Stokes breathing. Am J Physiol. 1956;187(2): 395-398. 3. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112. 4. Franklin KA, Sandström E, Johansson G, Bâlfors EM. Hemodynamics, cerebral circulation, and oxygen saturation in CheyneStokes respiration. J Appl Physiol. 1997;83(4):1184-1191. 5. Band DM, Wolff CB. Respiratory oscillations in discharge frequency of chemoreceptor afferents in sinus nerve and anaesthetized cats at normal and low arterial oxygen tensions. J Physiol. 1978;282:1-6. 6. Haouzi P, Ahmadpour N, Bell HJ, et al. Breathing patterns during cardiac arrest. J Appl Physiol. 2010;109(2):405-411.
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Selected Reports
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245. 2. Reboul MP, Bieth E, Fayon M, et al. Splice mutation 1811 1 1.6kbA.G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients. J Med Genet. 2002;39(11):e73. 3. Boucher RC. Cystic fibrosis: a disease of vulnerability to airway surface dehydration. Trends Mol Med. 2007;13(6): 231-240. 4. Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18): 1663-1672. 5. Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363(21):1991-2003. 6. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009;106(44): 18825-18830. 7. Yarlagadda S, Zhang W, Penmatsa H, et al. A young Hispanic with c.1646G.A mutation exhibits severe cystic fibrosis lung disease: is ivacaftor an option for therapy? Am J Respir Crit Care Med. 2012;186(7):694-696. 8. Durmowicz AG, Witzmann KA, Rosebraugh CJ, Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013;143(1): 14-18.
Periodic Breathing With No Heart Beat Stephen Bartsch, MD; and Philippe Haouzi, MD
A protocol was originally designed to study breathing control during and following cardiac arrest in humans, taking advantage of the period of pulseless ventricular fibrillation (PVF) produced while testing a newly implanted cardioverter-defibrillator device. A patient aged in his 60s with New York Heart Association class III heart failure (HF) (left ventricular ejection fraction of 25%) who was originally part of this study displayed permanent periodic breathing (PB) and was
then excluded from the final data analysis; his response is presented in this report. The 8- to 9-s PVF was incidentally produced during the ascending phase of a PB cycle, followed by another 12-s recovery period of low BP. PVF and its recovery had no effect on PB characteristics (period or amplitude). This occurred despite a profound change in PACO2, cerebral blood flow, and perfusion of the carotid bodies. It is concluded that PB in patients with HF could be produced by primary oscillations originating from the central pattern generator. CHEST 2013; 144(4):1378–1380 Abbreviations: CB 5 carotid body; HF 5 heart failure; ICD 5 implantable cardioverter-defibrillator device; PB 5 periodic breathing; PVF 5 pulseless ventricular fibrillation
T
he mechanisms believed to cause periodic breathing (PB) in patients with heart failure (HF) include enhanced gain of the carotid bodies (CBs),1 increased circulatory time,2 periodic variations in cerebral blood flow-induced brainstem changes in pH,3 or primary oscillating mechanisms within the central pattern generator for breathing.4 Although many of these mechanisms can be reproduced experimentally and can lead to breathing instability, there is still a vivid debate on the frame of reference to be used to understand PB in patients with HF.3 We had the opportunity to record the breathing pattern of a male patient aged in his 60s with New York Heart Association class III HF (left ventricular ejection fraction of 25%) who displayed long periods of PB (with cycles lasting from 40-50 s). This patient, who had no history of stroke or other neurologic deficit traditionally associated with PB, was originally part of an institutional review board-approved study on the control of breathing during cardiac arrest. This patient was excluded from that study because of the lack of stable baseline ventilation. The procedure consisted of a subcutaneous placement of an implantable cardioverter-defibrillator device (ICD) (Intrinsic DR ICD generator; Medtronic, Inc) for standard clinical indications under IV conscious sedation with propofol (diisopropylphenol). Inspiratory and expiratory flows were measured via a low-dead-space face mask connected to a pneumotachograph (Fleisch Pneumotachograph # 2; Phipps & Bird, Inc). Expired CO2 was continuously measured, and end-tidal Pco2 (Paco2) was determined using a fast infrared CO2 analyzer (VacuMed). The ventilatory variables were recorded (PowerLab; ADInstruments) along with BP (Finapres Medical Systems BV) and the ECG during Manuscript received December 8, 2012; revision accepted March 12, 2013. Affiliations: From the Division of Pulmonary and Critical Care Medicine, Penn State University College of Medicine, Penn State Hershey Medical Center, Hershey, PA. Part of this article has been presented in abstract form (Bartsch S, Haouzi P. Am J Respir Crit Care Med. 2012;185:A2053). Correspondence to: Philippe Haouzi, MD, Penn State University College of Medicine, Penn State Hershey Medical Center, Division of Pulmonary and Critical Care Medicine, 500 University Dr, Hershey, PA 17033; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2950
1378
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Selected Reports
the entire procedure of ICD placement. In accordance with standard clinical protocols, the ICD was tested at the end of the procedure by the induction of pulseless ventricular fibrillation (PVF) (high-frequency burst pacing, 50 Hz, 8 V), allowing for the appropriate discharge of the device to restore sinus rhythm. The episode of PFV occurred during the ascending phase of a PB cycle (Fig 1) leading to a dramatic drop in BP (Fig 1) for 8 to 9 s. This period of asystole was followed by a period of low BP for another 12 s after defibrillation. At the very onset of a cardiac arrest, systemic peripheral blood flow is certainly not instantaneously null, as pressures between the arterial compartment (in which the pressure drops) and the venous system (wherein pressure increases) will slowly equilibrate until the mean filling pressure is reached, creating some peripheral blood flow; however, as soon as the cardiac pump stops, systemic blood flow is expected to reach a level difficult to reconcile with any significant form of gas transport. Therefore, blood flow must have been severely reduced for . 20 s after the onset of PFV. Despite the expected reduction in both pulmonary and
systemic blood flow, PVF had no visible effect on the periodicity or the amplitude of this or the subsequent PB cycles ( Fig 1 ). Yet, the reduction in blood flow to the carotid chemoreceptors during the period of PVF should have erased the intrabreath oscillations in Paco2-induced CB stimulation.5 In addition, this reduction in systemic blood flow should have also reset any PB pattern, which would have been caused by cerebral blood flow oscillations and/or circulatory delay.3 Upon the slow return to normal circulatory conditions, the blood leaving the pulmonary circulation is expected to have been transiently hypocapnic and hyperoxic, as a result of the persistent ventilatory activity with no (then low) pulmonary blood flow.6 Indeed, as the entire period of PVF occurred during the ascending phase of a PB cycle, the rise in end-tidal Pco2 that occurred typically before the peak of the breathing oscillations was abolished following defibrillation. As shown in Figure 1, this led to a reduction in alveolar Pco2 by 7 mm Hg during the PB cycle, when PVF was triggered, compared with other BP cycles. Perhaps more importantly, the prolonged reduction in systemic venous return and arterial supply during the
Figure 1. A, Recording obtained during implanted cardioverter-defibrillator device (ICD) replacement. The following signals are displayed: end-tidal CO2 fraction, respiratory flow, tidal volume, continuous noninvasive BP, and ECG. The entire period of pulseless ventricular fibrillation (PVF) PVF (between the two vertical arrows) incidentally occurred during the ascending phase of a PB cycle. Note that ICD discharge caused a very brief muscle contraction of the chest wall with a transient artifact on the airflow, BP, and ECG signals. The periods of induced PVF and its recovery following the firing of the implantable cardiac defibrillator lasted for 20 s or so, whereas the temporal profile, periodicity, and amplitude of PB were not affected (see also C). B, Magnification of the period of cardiac arrest and defibrillation showing end-tidal CO2, BP, respiratory flow, and mean BP signals. Clearly, BP, and, thus, blood flow, remained low beyond the period of PVF (ie, for ⱖ 10 s after defibrillation). C, End-tidal CO2 and respiratory flow signals of the PB cycle during which PVF (black line) was produced, superimposed on the subsequent PB cycle (red line). Note that despite a difference in Paco2 by approximately 7 mm Hg and the additional delay in circulatory time during the loss and return of spontaneous circulation, PB pattern was not affected except for a transient alteration of two breaths, which occurred during defibrillation. *Artifact on the Finapres BP signal. Feco2 5 end-tidal CO2 fraction; 5 respiratory flow; Vt 5 tidal volume. journal.publications.chestnet.org
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period of PVF and its subsequent slow recovery must have resulted in a continuous, rather than oscillatory, stimulation of the central chemoreceptors as tissue CO2 accumulates and local acidosis develops. This continuous stimulation should have produced a distortion in PB oscillations, which we did not observe. Therefore, the present observation is difficult to reconcile with the theories assuming that PB can be produced and maintained via a prolonged circulatory delay, change in the gain of the CB, or the consequences of periodic fluctuations in cerebral blood flow. This intriguing observation of unchanged PB during and following cardiac arrest suggests that a primary oscillating central mechanism could be the main controller of breath cycles in PB, at least in some patients with HF.5
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Topor ZL, Vasilakos K, Younes M, Remmers JE. Model based analysis of sleep disordered breathing in congestive heart failure. Respir Physiol Neurobiol. 2007;155(1):82-92. 2. Crowell JW, Guyton AC, Moore JW. Basic oscillating mechanism of Cheyne-Stokes breathing. Am J Physiol. 1956;187(2): 395-398. 3. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112. 4. Franklin KA, Sandström E, Johansson G, Bâlfors EM. Hemodynamics, cerebral circulation, and oxygen saturation in CheyneStokes respiration. J Appl Physiol. 1997;83(4):1184-1191. 5. Band DM, Wolff CB. Respiratory oscillations in discharge frequency of chemoreceptor afferents in sinus nerve and anaesthetized cats at normal and low arterial oxygen tensions. J Physiol. 1978;282:1-6. 6. Haouzi P, Ahmadpour N, Bell HJ, et al. Breathing patterns during cardiac arrest. J Appl Physiol. 2010;109(2):405-411.
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Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 10/03/2013
Selected Reports