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Helium-oxygen reduces the production of carbon dioxide during weaning from mechanical ventilation.
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MedLine Citation:
PMID:  20796307     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Prolonged weaning from mechanical ventilation has a major impact on ICU bed occupancy and patient outcome, and has significant cost implications.There is evidence in patients around the period of extubation that helium-oxygen leads to a reduction in the work of breathing. Therefore breathing helium-oxygen during weaning may be a useful adjunct to facilitate weaning. We hypothesised that breathing helium-oxygen would reduce carbon dioxide production during the weaning phase of mechanical ventilation.
MATERIALS/PATIENTS AND METHODS: We performed a prospective randomised controlled single blinded cross-over trial on 19 adult intensive care patients without significant airways disease who fulfilled criteria for weaning with CPAP. Patients were randomised to helium-oxygen and air-oxygen delivered during a 2 hour period of CPAP ventilation. Carbon dioxide production (VCO2) was measured using a near patient main stream infrared carbon dioxide sensor and fixed orifice pneumotachograph.
RESULTS: Compared to air-oxygen, helium-oxygen significantly decreased VCO2 production at the end of the 2 hour period of CPAP ventilation; there was a mean difference in CO2 production of 48.9 ml/min (95% CI 18.7-79.2 p = 0.003) between the groups. There were no significant differences in other respiratory and haemodynamic parameters.
CONCLUSION: This study shows that breathing a helium-oxygen mixture during weaning reduces carbon dioxide production. This physiological study supports the need for a clinical trial of helium-oxygen mixture during the weaning phase of mechanical ventilation with duration of weaning as the primary outcome.
TRIAL REGISTRATION: ISRCTN56470948.
Authors:
Gordon Flynn; Gerlinde Mandersloot; Marie Healy; Mark Saville; Daniel F McAuley
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Publication Detail:
Type:  Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2010-08-26
Journal Detail:
Title:  Respiratory research     Volume:  11     ISSN:  1465-993X     ISO Abbreviation:  Respir. Res.     Publication Date:  2010  
Date Detail:
Created Date:  2010-09-17     Completed Date:  2011-06-01     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  101090633     Medline TA:  Respir Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  117     Citation Subset:  IM    
Affiliation:
Intensive Care Unit, Royal London Hospital, Whitechapel, London, E1 1BB, UK. Gordon.Flynn@sesiahs.health.nsw.gov.au
Data Bank Information
Bank Name/Acc. No.:
ISRCTN/ISRCTN56470948
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Aged, 80 and over
Carbon Dioxide / antagonists & inhibitors*,  metabolism*
Cross-Over Studies
Helium / administration & dosage*
Humans
Middle Aged
Oxygen / administration & dosage*
Prospective Studies
Respiration, Artificial / methods
Single-Blind Method
Ventilator Weaning / methods*
Young Adult
Chemical
Reg. No./Substance:
124-38-9/Carbon Dioxide; 7440-59-7/Helium; 7782-44-7/Oxygen
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Respir Res
ISSN: 1465-9921
ISSN: 1465-993X
Publisher: BioMed Central
Article Information
Copyright ©2010 Flynn et al; licensee BioMed Central Ltd.
open-access:
Received Day: 15 Month: 11 Year: 2009
Accepted Day: 26 Month: 8 Year: 2010
Print publication date: Year: 2010
Electronic publication date: Day: 26 Month: 8 Year: 2010
Volume: 11 Issue: 1
First Page: 117 Last Page: 117
Publisher Id: 1465-9921-11-117
PubMed Id: 20796307
DOI: 10.1186/1465-9921-11-117

Helium-oxygen reduces the production of carbon dioxide during weaning from mechanical ventilation
Gordon Flynn13 Email: Gordon.Flynn@sesiahs.health.nsw.gov.au
Gerlinde Mandersloot1 Email: Gerlinde.Mandersloot@bartsandthelondon.nhs.uk
Marie Healy1 Email: marie.healy@bartsandthelondon.nhs.uk
Mark Saville1 Email: markjsaville@hotmail.com
Daniel F McAuley2 Email: d.f.mcauley@qub.ac.uk
1Intensive Care Unit, Royal London Hospital, Whitechapel, London, E1 1BB, UK
2Respiratory Medicine Research Programme, Centre for Infection and Immunity, The Queen's University of Belfast, Grosvenor Road, BT12 6BN, Belfast, Northern Ireland
3Intensive Care Unit, Prince of Wales Hospital, Barker Street, Sydney, NSW, 2031, Australia

Introduction

Weaning from mechanical ventilation is estimated to account for up to 40% of the total duration of ventilatory support [1]. The process of weaning patients therefore has a major impact on ICU bed occupancy with significant cost implication [2]. Strategies to facilitate weaning have a major potential to reduce use of healthcare resources [3,4].

Helium is an inert gas and prolonged administration to animals has demonstrated no adverse effects [5]. Helium has a lower density and higher viscosity compared with oxygen and nitrogen. Breathing helium leads to a decreased resistance in gas flow, a change from turbulent to laminar flow patterns [6] and a reduction in the work of breathing. However a change from turbulent to laminar flow patterns is unnecessary for the reduction in the work of breathing which can occur under fully turbulent flow [7].

Helium-oxygen has been used in clinical situations where upper or lower airways obstruction or disease leads to an increased resistance to flow. Although there are many case reports of successful use of helium-oxygen in these conditions, to date no studies have conclusively demonstrated improved outcomes in these patient groups [8].

There are limited data regarding the use of helium-oxygen during weaning. Use of a helium-oxygen mixture during weaning with CPAP has been successfully used to improve respiratory distress and improve PaO2 after cardiovascular surgery in a small study in infants [9]. In addition, in ventilated patients with airflow obstruction, breathing helium-oxygen during a T-piece breathing trial just prior to extubation resulted in a reduction in airway resistance and consequently a decrease in work of breathing [10].

The aim of this physiological study was to determine whether breathing a helium-oxygen mixture as compared with an air-oxygen mixture during the weaning phase of mechanical ventilation would reduce carbon dioxide production in patients without significant airways obstruction.


Materials and methods

We conducted a prospective single centre, randomised, single blinded, controlled, cross-over study in our 18 bed mixed medical-surgical ICU. Approval for the study was obtained from Research Ethics Committee and the Medicines and Health Regulatory Agency (MHRA). Eligible patients were ready for weaning to CPAP and had to meet the following inclusion criteria; the underlying cause of respiratory failure was improving, pressure support ventilation of less than 10 cmH2O, no continuous intravenous sedation or inotropes, FiO2 less than or equal to 0.4 and requiring less than 10 cmH2O positive end expiratory pressure. Written informed consent from the patient or assent from their next of kin was obtained.

Respiratory parameters were measured using a near patient main stream infrared carbon dioxide sensor and fixed orifice pneumotachograph connected to a respiratory profile monitor (CO2SMO Plus Respiratory Monitor, Novametrix Medical systems, Wallingford, CT, USA) and analysed using computer software (Analysis plus). The capnograph is barometric pressure compensated with an accuracy of +/- 2 mmHg (for 0 - 40 mmHg) and +/- 5% of the reading (for 41 - 70 mmHg). The pneumotachograph is a disposable device using differential pressure with an overall accuracy of +/-2%. This device was calibrated for the specific fraction of inspired helium and oxygen on an individual patient basis according to the manufacturer's instructions. On initialisation the device performs a zero calibration. The accuracy of the infrared carbon dioxide sensor is further verified by using a calibration device for carbon dioxide. Furthermore a previous study showed the monitoring device remained stable and accurate over a 48 hour period of continuous monitoring[11]. Alveolar minute ventilation, respiratory rate and CO2 production were continuously recorded by the CO2SMO plus monitor. Representative base line carbon dioxide production in a 70 kg male is 200 ml/min. An average of a 5 minute period of these parameters was recorded before the start of CPAP as a baseline and at 1 and 2 hours during each CPAP period with the study gases. Systolic and diastolic blood pressure and heart rate were recorded directly by means of an indwelling arterial catheter and electrocardiogram (ECG) attached to a bedside monitor. Arterial partial pressure of carbon dioxide and oxygen were obtained over a 2-hour period from arterial blood gas samples.

Patients were randomly assigned to initially breath either Heliox or air-oxygen mixtures. Patients were blinded to the gas mixture they received. Data was collected directly to a laptop computer and the researcher and study statistician who analysed the data were blinded to the gas mixtures. Following baseline measurements, patients received 2 hours of CPAP ventilation (PEEP setting remained unchanged and pressure support set to zero) with helium-oxygen or air-oxygen via an eVent ventilator (eVent Medical Inc. 81 Columbia Suite 101, Aliso Viejo, CA 92656). This ventilator was calibrated for the helium oxygen mixture on an individual patient basis according to the manufacturer's instructions. Patients were returned to their pre study ventilator settings for 2 hours, before being given the alternative gas mixture for 2 hours.

The level of CPAP support and FiO2 were unchanged for individual patients throughout the trial period. The study CPAP trial was defined as unsuccessful and discontinued if the patients developed two or more of the following criteria: respiratory rate > 40 breaths/min or rapid shallow breathing index (RSBI) > 105; SpO2 <90% or SpO2 decrease to >8% from the patients baseline value; HR > 140 beats/min or HR changes by >20% from the patients baseline; systolic blood pressure >200 mmHg or < 80 mmHg or systolic blood pressure changes by >20% of baseline; deterioration in conscious level, defined as a fall in GCS of >2, or if the patient became agitated/sweating/anxious.

The data were tested for normality and a paired t-test was used to test the treatment effect on within-subject differences. A priori the 2-hour time point was used as a summary measure of treatment effect. The data were expressed as means, standard deviations (SD) and 95% confidence intervals (CI). A p-value of < 0.05 was considered statistically significant.


Results

Twenty-three patients were recruited into the study. A total of 19 completed the study protocol and their baseline characteristics are displayed in Table 1. Patients were treated with mechanical ventilation for a median 9 days (inter-quartile range, IQR, 6-12 days). The primary underlying condition was neurological in 8 patients, medical in 4 patients, polytrauma in 6 patients with 1 surgical patient. One patient was recruited with an infective exacerbation of COPD.

Four patients did not have evaluable data and were not included in the analysis. One patient became anxious when commenced on CPAP and withdrew consent (helium-oxygen), in 2 patients the respiratory rates exceeded the protocol within 15 minutes of commencing CPAP and were returned to their pre-study ventilatory support (1 helium-oxygen, 1 air-oxygen) and 1 patient was randomised but developed epileptic seizures just prior to starting CPAP and was withdrawn. Fifteen of the patients were studied on an FiO2 of 0.3 or less, three patients were on an FiO2 0.35 and one patient on an FiO2 of 0.4. Nine patients received helium-oxygen mixture first compared to ten receiving air-oxygen first.

Compared to air-oxygen, helium-oxygen significantly decreased VCO2 production at the end of the 2 hour period of CPAP ventilation (Figure 1) There was a mean difference in CO2 production of 48.9 ml/min (95% CI 18.7-79.2 p = 0.003) between the groups. There were no significant differences between baseline and 2 hours CPAP with air-oxygen and helium-oxygen in all other respiratory and heamodynamic parameters measured (Table 2).


Discussion

Our study showed a significant reduction in CO2 production in patients without significant airways disease. This supports the need for a definitive clinical study of Heliox in weaning from mechanical ventilation to be undertaken. We were surprised by the 19% reduction in CO2 production seen while breathing helium oxygen although this is in keeping with a 21% reduction in work of breathing shown by Diehl et al in their study [10]

Weaning from mechanical ventilation has a major impact on ICU bed occupancy and patient outcome, and has significant cost implications. Strategies to facilitate weaning have a major potential to improve patient outcome and reduce the use of healthcare resources. We demonstrate in this physiological study that patients weaning from mechanical ventilation show a significant reduction in carbon dioxide production when breathing a helium-oxygen mixture. We found that all other respiratory and cardiovascular parameters measured showed no significant changes from baseline values.

In our study we used CO2 production as a surrogate for the work of breathing. Studies have confirmed that inspiratory muscular work of breathing is proportional to the exhaled volume of CO2 per minute after allowing a period of time for stabilisation of CO2 [12-14]. Our findings are consistent with previous studies using helium-oxygen in intubated patients with COPD during controlled ventilation and on pressure support ventilation during the weaning phase of ventilation [15,16]. These studies have shown a reduction in total, resistive and elastic work of breathing with helium-oxygen mixtures. In spontaneously breathing patients with COPD during a T-piece trial there was a reduction in work of breathing from 1.4 to 1.1 J/L in 13 patients with COPD and a reduction in intrinsic positive end expiratory pressure PEEPi [10]. Change in flow from turbulent to transitional or laminar by the use of the less dense helium is thought to be a major reason for improvement in gas flow. However, a study by Papamoschou, demonstrated that helium-oxygen does not need to be laminar to improve flow and benefits exist even if flow remains turbulent [7]. In a study in 18 patients without COPD studied immediately post-extubation, helium-oxygen given for 15 minutes reduced inspiratory effort as measured by transdiaphragmatic pressure changes. A significant subjective improvement in respiratory comfort was also observed. This benefit reversed when patients were returned to air-oxygen [17]. However as patients were already weaned to the point of extubation, no conclusion can be drawn as to whether helium-oxygen improved the weaning phase. A further small study of helium use in infants post-cardiac surgery, during weaning, showed a reduction in CO2 production and an increase in PaO2 reflecting a reduction in work of breathing [9]. Our current study extends these previous data to a group of general adult intensive care unit patients without significant airways disease during the weaning phase of mechanical ventilation. While this physiological study has demonstrated a beneficial but transient effect on CO2 production with the short-term use of a helium mixture, future studies designed to investigate the effect on duration of weaning would require longer term use of helium mixture.

It is worth noting that helium can interfere with the function of ventilators and in particular, flow measurement devices. It is therefore important that clinicians are aware of the effects helium can have on the equipment they use, and equipment must be compatible with, and calibrated for, use with helium [18].

This study has several limitations. The aim of this physiological study was to measure CO2 production in patients without documented obstructive airways disease. It is not possible to exclude that a proportion of the patients had unrecognised small airways obstruction. The study is limited by the small number of patients and one patient had a documented history of COPD. Importantly when this patient is removed from the analysis the beneficial effect of helium-oxygen is still significant. In addition, we used CO2 production as a surrogate for work of breathing. Carbon Dioxide production is one of the indirect calorimetric methods of measuring metabolic rate. Factors other than work of breathing that increase metabolic rate will likely increase CO2 production. No changes to the physical workload of our patients were made during the study period. Furthermore there was no difference in other measured respiratory and haemodynamic parameters or temperature as shown in Table 2. This indirectly indicates that the change in CO2 production is likely to indirectly reflect work of breathing. Measurements of trans-oesophageal pressures or pressure-volume loop would have been useful to more directly assess work of breathing but unfortunately these were not available.

In conclusion, our study demonstrated a significant reduction in CO2 production, as a surrogate measure of work of breathing, in adult patients during the weaning phase of ventilation breathing a helium-oxygen mixture. This provides support for a clinical study powered for duration of weaning as the primary outcome to be undertaken.


Abbreviations

CO2: carbon dioxide; COPD: chronic obstructive pulmonary disease; CPAP: continuous positives airway pressure; DBP: diastolic blood pressure; FiO2: fraction inspired oxygen; HR: heart rate; RR: respiratory rate; NS: non significant; PEEPi: positive end expiratory pressure intrinsic; SBP: systolic blood pressure; RSBI: rapid shallow breathing index.


Competing interests

The authors declare they have no competing interests. The Royal London Hospital received an unrestricted £10,000 grant from BOC to support this study which was used to purchase the CO2MO monitor. Two ventilators were loaned by BOC to the hospital for the duration of the study.


Authors' contributions

GF participated in the study design and set up, recruitment of patients, data collection and manuscript writing. GM, MH, MS participated in patient recruitment, data collection, review of the manuscript. DM participated in study design, coordination and set up and review of the manuscript 'All authors read and approved the final manuscript.'


Acknowledgements

The authors would like to thank all the staff from the ICU who participated in this study. Dr Fiona Warburton Statistician, Joint R&D Office Barts & the London NHS Trust.


References
Esteban A,Alia I,Ibanez J,Benito S,Tobin MJ,Modes of mechanical ventilation and weaning. A national survey of Spanish hospitals. The Spanish Lung Failure Collaborative GroupChestYear: 19941061188119310.1378/chest.106.4.11887924494
MacIntyre NR,Cook DJ,Ely EW Jr,et al. Evidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care MedicineChestYear: 2001120375S395S10.1378/chest.120.6_suppl.375S11742959
Esteban A,Frutos F,Tobin MJ,et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative GroupN Engl J MedYear: 199533234535010.1056/NEJM1995020933206017823995
MacIntyre NR,Evidence-based ventilator weaning and discontinuationRespir CareYear: 20044983083615222913
Barach AL,Use of Helium as a New Therapeutic GasYear: 1934462464
Otis AB,Bembower WC,Effect of gas density on resistance to respiratory gas flow in manJ Appl PhysiolYear: 1949230030615403654
Papamoschou D,Theoretical validation of the respiratory benefits of helium-oxygen mixturesRespir PhysiolYear: 19959918319010.1016/0034-5687(94)00071-77740207
Colebourn CL,Barber V,Young JD,Use of helium-oxygen mixture in adult patients presenting with exacerbations of asthma and chronic obstructive pulmonary disease: a systematic reviewAnaesthesiaYear: 200762344210.1111/j.1365-2044.2006.04897.x17156225
Tatsuno K,Imai Y,Konno S,Therapeutic use of helium-oxygen mixture in continuous positive airway pressure for early weaning from mechanical ventilation after cardiovascular surgery in infantsJ Thorac Cardiovasc SurgYear: 197672119122778498
Diehl JL,Mercat A,Guerot E,et al. Helium/oxygen mixture reduces the work of breathing at the end of the weaning process in patients with severe chronic obstructive pulmonary diseaseCrit Care MedYear: 2003311415142010.1097/01.CCM.0000059720.79876.B512771612
Rockmann F,Evaluation of a new combined CO2 and respiratory monitoring systemClinical intensive care edYear: 200412312910.1080/09563070400005438
Arnold JH,Thompson JE,Arnold LW,Single breath CO2 analysis: description and validation of a methodCrit Care MedYear: 1996249610210.1097/00003246-199601000-000178565546
Sutton PJ,Perkins CL,Giles SP,McAuley DF,Gao F,Randomised controlled cross-over comparison of continuous positive airway pressure through the Hamilton Galileo ventilator with a Drager CF 800 deviceAnaesthesiaYear: 200560727610.1111/j.1365-2044.2004.04030.x15601276
Taskar V,John J,Larsson A,Wetterberg T,Jonson B,Dynamics of carbon dioxide elimination following ventilator resettingChestYear: 199510819620210.1378/chest.108.1.1967606958
Gainnier M,Arnal JM,Gerbeaux P,Donati S,Papazian L,Sainty JM,Helium-oxygen reduces work of breathing in mechanically ventilated patients with chronic obstructive pulmonary diseaseIntensive Care MedYear: 2003291666167010.1007/s00134-003-1911-z12897990
Tassaux D,Gainnier M,Battisti A,Jolliet P,Helium-oxygen decreases inspiratory effort and work of breathing during pressure support in intubated patients with chronic obstructive pulmonary diseaseIntensive Care MedYear: 2005311501150710.1007/s00134-005-2796-916172846
Jaber S,Carlucci A,Boussarsar M,et al. Helium-oxygen in the postextubation period decreases inspiratory effortAm J Respir Crit Care MedYear: 200116463363711520728
Tassaux D,Jolliet P,Thouret JM,Roeseler J,Dorne R,Chevrolet JC,Calibration of seven ICU ventilators for mechanical ventilation with helium-oxygen mixturesAm J Respir Crit Care MedYear: 1999160223210390375

Figures

[Figure ID: F1]
Figure 1 

Carbon dioxide production over time in hours for heliox and air.



Tables
[TableWrap ID: T1] Table 1 

Patient characteristics


Patient number Age Primary reason condition Secondary reason condition APACHE II Status at unit discharge Length of unit stay (rounded) Length mechanical ventilation till inclusion
1 21 Status epilepticus or uncontrolled seizures 17 Alive 11 9
2 77 Pulmonary haemorrhage not defined Thoracic or thoraco-abdominal aortic aneurysm 22 Alive 21 12
3 84 Inhalation pneumonitis (smoke or gases) 19 Alive 11 12
4 44 Pneumonia, no organism isolated Depression 14 Alive 9 5
5 84 Haemorrhage or haematoma from pelvis, long bones or joints Fractured ribs 23 Alive 30 12
6 65 Intracerebral haemorrhage Secondary hydrocephalus 20 Alive 5 2
7 30 Traumatic rupture or laceration of liver Hypovolaemic shock 16 Alive 17 13
8 68 Lung collapse or atelectasis Lung abscess 16 Alive 23 6
9 46 Primary (diffuse) brain injury Lumbar spine fracture or ligamentous injury 25 Alive 27 26
10 47 Primary (diffuse) brain injury Amputation of limb 15 Alive 10 6
11 72 Primary (diffuse) brain injury Traumatic subarachnoid haemorrhage 19 Alive 9 7
12 76 Abdominal aortic aneurysm, ruptured Acute renal failure due to haemodynamic causes 18 Dead 12 7
13 45 Primary (diffuse) brain injury Pneumonitis due to food and vomit 10 Alive 13 10
14 18 Traumatic myocardial perforation Anoxic or ischaemic coma or encephalopathy 12 Alive 22 17
15 36 Tracheal trauma or perforation Traumatic pneumothorax 19 Alive 20 12
16 28 Traumatic subdural haemorrhage Focal brain injury 9 Alive 10 8
17 58 Chronic obstructive pulmonary disease with acute exacerbation, unspecified 15 Alive 3 1
18 79 Traumatic subdural haemorrhage 28 Alive 6 4
19 67 Pneumonia, no organism isolated Pleural effusion 24 Alive 12 9
Mean 53.3 17.3 13.9 9.2
SD 21.7 5.0 7.6 5.7
Median 9

IQR 6-12

[TableWrap ID: T2] Table 2 

Respiratory and haemodynamic parameters during the study period


Baseline Helium/oxygen after 2 hours CPAP Baseline Air/oxygen after 2 hours CPAP Statistical significance
RR, breaths/min 24 +/- 7 25 +/- 5 26 +/- 6 25 +/- 6 NS
PaCO2, kPa 5.2 +/- 1.0 5.2 +/- 1.0 5.4 +/- 1.1 5.4 +/- 1.2 NS
PaO2, kPa 11.3 +/- 2.1 11.2 +/- 1.8 12.7 +/- 2.3 11.7 +/- 2.4 NS
Minute volume 10.2 +/- 2.8 10.8 +/- 2.5 10.6 +/- 2.3 10.2 +/- 2.4 NS
HR, beats/min 89 +/- 14 89 +/- 13 88 +/- 14 91 +/- 14 NS
SBP, mmHg 128 +/- 27 126 +/- 23 126 +/- 23 130 +/- 27 NS
DBP, mmHg 63 +/- 8 62 +/- 10 63 +/- 11 65 +/- 12 NS
Temperature 37 +/- 1 37 +/- 1 37+/- 1.5 37 +/- 1 NS

Definitions of abbreviations; RR = respiratory rate; HR = heart rate; SBP = systolic blood pressure; DBP = diastolic blood pressure; NS = non significant.

Values are means +/- standard deviation



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