Autonomic Nervous System Dysfunction in Critically IllNCT01930669
Transplanted-like Heart in Critical Ill Patients
A study testing Gravitational sympathetic stimulus in people with Autonomic Nervous System Dysfunction in Critically Ill, run by ASST Fatebenefratelli Sacco at 2 sites in Italy.
Trial summary
The purpose of this study is to measure the dysfunction of the autonomic nervous system in modulating the heart rate variability and baroreflex control in critically ill. Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Autonomic Nervous System Dysfunction in Critically Ill
- What is being tested?
- Gravitational sympathetic stimulus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 150 participants
- Where
- 2 sitesItaly
- Study dates
- Aug 2013to Sep 2014
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Patients admitted in ICU with
- age between 18 and 75 years
- expected length of stay in ICU >24 hours
- sinus rhythm on ECG
- ectopic heart beats <5% of all heart beats
- no contraindications of any kind to head-up 60 degrees position
Who cannot join
- age <18 and >75 years
- elective postoperative patients
- non sinusal rhythm of ECG
- ectopic heart beats >5% of all heart beats
- spinal or head injury
- suspected or documented intracranial hypertension
- contraindications of any kind to head up 60 degrees position
Trial locations and contacts
2 sites in 1 country.
Italy2 sites
Azienda Ospedaliera "Luigi Sacco" - Polo Universitario - University of Milan
Milan, 20157
Istituto Clinico Humanitas
Rozzano, 20089
About this study
The purpose of this study is to measure the dysfunction of the autonomic nervous system in modulating the heart rate variability and baroreflex control in critically ill.
Read the detailed description
Autonomic nervous system (ANS) is able to change both heart beat-to-beat interval and peripheral muscle vascular tone in response to different stimuli. Unfortunately the direct measure of the sympathetic and vagal activity appears not feasible in a clinical setting. ANS modulation is studied non-invasively by means of heart rate variability (HRV) and baroreflex sensitivity. Decreased HRV has been found in critical ill patients with multiple organ dysfunction syndrome (MODS) and sepsis, thus it has been supposed being a sign of autonomic dysfunction. Frequently, in mechanically ventilated critical ill patients the HRV does not show any oscillatory pattern, as well as it appears in the early months after heart transplantation. Under these circumstances the heart seems to lack the neuro-modulatory control by ANS and it seems to respond exclusively to the preload and afterload laws. This could have implications for outcome because autonomic dysfunction is associated with increasing severity of illness and mortality. Since the ANS modulation is a dynamic process that implies a central integration of a complex variety of afferent stimuli (from carotid sinus, cardiopulmonary receptors, pain,…) and efferences through sympathetic and vagal branches, up to the present it is unclear if in critically ill a reduced HRV at rest reflects a state of low requirement of ANS modulation or truly a failure of the ANS. To provide new insights into this important topic we study the changes of ANS modulation in response to a orthostatic sympathetic stimulus daily from the day of ICU admission until day 28, or the day of discharge from ICU if it occurs before the day 28.
Measurements. Beat-to-beat intervals are computed detecting the QRS complex on the electrocardiogram and locating the R-apex using parabolic interpolation. The maximum arterial pressure within each R-to-R interval is taken as systolic arterial pressure (SAP). Sequences of 300 values are randomly selected inside each experimental condition. The power spectrum is estimated according to a univariate parametric approach fitting the series to an autoregressive model. Autoregressive spectral density is factorized into components each of them characterized by a central frequency. A spectral component is labeled as low frequency (LF) if its central frequency is between 0.04 and 0.15 Hz, while it is classified as high frequency (HF) if its central frequency is between 0.15 and 0.4 Hz. The HF power of R-to-R series is utilized as a marker of vagal modulation directed to the heart , while the LF power of SAP series is utilized as a marker of sympathetic modulation directed to vessels. The ratio of the LF power to the HF power assessed from R-to-R series is taken as an indicator sympatho-vagal balance directed to the heart. Baroreflex control in the low frequencies is computed as the square root of the ratio of LF(RR) to LF(SAP). In the same way baroreflex control in the high frequencies is defined as the square root of the ratio of HF(RR) to HF(SAP).
The experimental condition is a sequence of three time point each lasting 10 min: (i) rest, with patient in supine position at zero degree; (ii) modified tilt; (iii) recovery, with the patient supine.
- Being tested
- Gravitational sympathetic stimulus
- Keywords
- Heart Rate Variability, Multiple Organ Dysfunction Syndrome, Critically Ill
- Medical subject headings
- Multiple Organ Failure, Critical Illness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gravitational sympathetic stimulusOther
Autonomic nervous system (ANS) activity is assessed by means of HRV, SAP variability and baroreflex control analysis daily from day 1 to discharge from ICU or day 28.
Analysis is performed (i)at rest in supine position with bed at zero degrees of inclination (ii) during modified tilt (MTILT) and (iii) recovery from MTILT in supine position at zero degrees. In a subgroup of patients motor sympathetic nervous activity (MSNA) is recorded at day 1,2 and 7.
MTILT consists in elevating head and trunk of patients at 60 degrees and lowering legs at 15 degree with a standard critical care bed. MSNA is recorded from the external peroneal nerve with microneurographic technique.
| Study group | Role | What they receive |
|---|---|---|
| All patients | Other | To measure the autonomic nervous system activity elicited by a gravitational sympathetic stimulus in critically ill Receives: Other: Gravitational sympathetic stimulus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of autonomic nervous system dysfunction in critical ill patients
failure to change significantly HRV and baroreflex variables in response to MTILT.
Measured: from day 1 to day 28
Secondary outcomes (4)
to measure the occurrence of ANS failure in subgroups
subgroups: (i) sepsis; (ii) severe sepsis/ septic shock; (iii) failure affecting >1 organ as assessed by SOFA score; (iv) death/alive at ICU discharge We calculate the hazard ratio for each subgroup. We calculate the Cox's proportional model to identify the factors predisposing occurrence of ANS dysfunction/failure.
ANS failure definition: see secondary outcome
Measured: from day 1 to day 28
Length of stay in ICU and in Hospital
We measure length of stay in ICU and in hospital of patients without ANS dysfunction, with ANS dysfunction and with ANS failure
Measured: 8 months
mortality
We measure mortality among subgroups of patients ((i)without ANS dysfunction, (ii)with ANS dysfunction and (iii)with ANS failure), adjusted for severity of illness assessed with Simplified Acute Physiology Score(SAPSII)
Measured: 8 months
days free from mechanical ventilation
We measure days free from mechanical ventilation among patients without ANS dysfunction, with ANS dysfunction and with ANS failure
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2013 (estimated)
- Study startAug 2013
- Primary completionSep 2014
- Study completionSep 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Autonomic Nervous System Dysfunction in Critically IllStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 150 participants (actual)
Sponsor and investigators
- Lead sponsor
- ASST Fatebenefratelli Sacco
- Sponsor type
- University, hospital or other
- Collaborators
- Regione Lombardia
- Responsible party
- Principal investigator, Riccardo Colombo, ASST Fatebenefratelli Sacco
- Investigators
- Ferdinando Raimondi, Director, Study chair, Azienda Ospedaliera "L.Sacco"Riccardo Colombo, Consultant, Principal investigator, Azienda Ospedaliera "L.Sacco"Stefano Guzzetti, Director, Study director, Azienda Ospedaliera "L.Sacco"
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01930669
- Sponsor's protocol ID
- DR#13465/22Dec2011
- Status last verified
- Nov 2014
- First submitted
- 14 Aug 2013
- Last updated
- 5 Nov 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Mazzeo AT, La Monaca E, Di Leo R, Vita G, Santamaria LB. Heart rate variability: a diagnostic and prognostic tool in anesthesia and intensive care. Acta Anaesthesiol Scand. 2011 Aug;55(7):797-811. doi: 10.1111/j.1399-6576.2011.02466.x. Epub 2011 Jun 9.
PubMed 21658013Morris JA Jr, Norris PR, Waitman LR, Ozdas A, Guillamondegui OD, Jenkins JM. Adrenal insufficiency, heart rate variability, and complex biologic systems: a study of 1,871 critically ill trauma patients. J Am Coll Surg. 2007 May;204(5):885-92; discussion 892-3. doi: 10.1016/j.jamcollsurg.2007.01.019. Epub 2007 Mar 23.
PubMed 17481504Schmidt H, Hoyer D, Wilhelm J, Soffker G, Heinroth K, Hottenrott K, Said SM, Buerke M, Muller-Werdan U, Werdan K. The alteration of autonomic function in multiple organ dysfunction syndrome. Crit Care Clin. 2008 Jan;24(1):149-63, ix. doi: 10.1016/j.ccc.2007.10.003.
PubMed 18241783Wieske L, Kiszer ER, Schultz MJ, Verhamme C, van Schaik IN, Horn J. Examination of cardiovascular and peripheral autonomic function in the ICU: a pilot study. J Neurol. 2013 Jun;260(6):1511-7. doi: 10.1007/s00415-012-6818-6. Epub 2012 Dec 30.
PubMed 23275003Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res. 1986 Aug;59(2):178-93. doi: 10.1161/01.res.59.2.178.
PubMed 2874900Pagani M, Montano N, Porta A, Malliani A, Abboud FM, Birkett C, Somers VK. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation. 1997 Mar 18;95(6):1441-8. doi: 10.1161/01.cir.95.6.1441.
PubMed 9118511Porta A, Baselli G, Rimoldi O, Malliani A, Pagani M. Assessing baroreflex gain from spontaneous variability in conscious dogs: role of causality and respiration. Am J Physiol Heart Circ Physiol. 2000 Nov;279(5):H2558-67. doi: 10.1152/ajpheart.2000.279.5.H2558.
PubMed 11045994Furlan R, Porta A, Costa F, Tank J, Baker L, Schiavi R, Robertson D, Malliani A, Mosqueda-Garcia R; New Collective Author. Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus. Circulation. 2000 Feb 29;101(8):886-92. doi: 10.1161/01.cir.101.8.886.
PubMed 10694528Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL; New Collective Author. Human responses to upright tilt: a window on central autonomic integration. J Physiol. 1999 Jun 1;517 ( Pt 2)(Pt 2):617-28. doi: 10.1111/j.1469-7793.1999.0617t.x.
PubMed 10332107
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Transplanted-like Heart in Critical Ill Patients
- ClinicalTrials.gov ID
- NCT01930669
- Acronym / sponsor ID
- DR#13465/22Dec2011
- Keywords
- Heart Rate Variability, Multiple Organ Dysfunction Syndrome, Critically Ill
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 150 participants (actual)
- Lead sponsor
- ASST Fatebenefratelli SaccoUniversity, hospital or other
- Collaborators
- Regione Lombardia
- Study start
- Aug 2013
- Primary completion
- Sep 2014 (actual)
- Study completion
- Sep 2014 (actual)
- First posted
- 29 Aug 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to measure the dysfunction of the autonomic nervous system in modulating the heart rate variability and baroreflex control in critically ill.
Detailed description
Autonomic nervous system (ANS) is able to change both heart beat-to-beat interval and peripheral muscle vascular tone in response to different stimuli. Unfortunately the direct measure of the sympathetic and vagal activity appears not feasible in a clinical setting. ANS modulation is studied non-invasively by means of heart rate variability (HRV) and baroreflex sensitivity. Decreased HRV has been found in critical ill patients with multiple organ dysfunction syndrome (MODS) and sepsis, thus it has been supposed being a sign of autonomic dysfunction. Frequently, in mechanically ventilated critical ill patients the HRV does not show any oscillatory pattern, as well as it appears in the early months after heart transplantation. Under these circumstances the heart seems to lack the neuro-modulatory control by ANS and it seems to respond exclusively to the preload and afterload laws. This could have implications for outcome because autonomic dysfunction is associated with increasing severity of illness and mortality. Since the ANS modulation is a dynamic process that implies a central integration of a complex variety of afferent stimuli (from carotid sinus, cardiopulmonary receptors, pain,…) and efferences through sympathetic and vagal branches, up to the present it is unclear if in critically ill a reduced HRV at rest reflects a state of low requirement of ANS modulation or truly a failure of the ANS. To provide new insights into this important topic we study the changes of ANS modulation in response to a orthostatic sympathetic stimulus daily from the day of ICU admission until day 28, or the day of discharge from ICU if it occurs before the day 28.
Measurements. Beat-to-beat intervals are computed detecting the QRS complex on the electrocardiogram and locating the R-apex using parabolic interpolation. The maximum arterial pressure within each R-to-R interval is taken as systolic arterial pressure (SAP). Sequences of 300 values are randomly selected inside each experimental condition. The power spectrum is estimated according to a univariate parametric approach fitting the series to an autoregressive model. Autoregressive spectral density is factorized into components each of them characterized by a central frequency. A spectral component is labeled as low frequency (LF) if its central frequency is between 0.04 and 0.15 Hz, while it is classified as high frequency (HF) if its central frequency is between 0.15 and 0.4 Hz. The HF power of R-to-R series is utilized as a marker of vagal modulation directed to the heart , while the LF power of SAP series is utilized as a marker of sympathetic modulation directed to vessels. The ratio of the LF power to the HF power assessed from R-to-R series is taken as an indicator sympatho-vagal balance directed to the heart. Baroreflex control in the low frequencies is computed as the square root of the ratio of LF(RR) to LF(SAP). In the same way baroreflex control in the high frequencies is defined as the square root of the ratio of HF(RR) to HF(SAP).
The experimental condition is a sequence of three time point each lasting 10 min: (i) rest, with patient in supine position at zero degree; (ii) modified tilt; (iii) recovery, with the patient supine.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| All patients | Other | Other: Gravitational sympathetic stimulusTo measure the autonomic nervous system activity elicited by a gravitational sympathetic stimulus in critically ill |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Patients admitted in ICU with
- age between 18 and 75 years
- expected length of stay in ICU >24 hours
- sinus rhythm on ECG
- ectopic heart beats <5% of all heart beats
Key exclusion criteria (7 listed)
- age <18 and >75 years
- elective postoperative patients
- non sinusal rhythm of ECG
- ectopic heart beats >5% of all heart beats
- spinal or head injury
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gravitational sympathetic stimulusAutonomic nervous system (ANS) activity is assessed by means of HRV, SAP variability and baroreflex control analysis daily from day 1 to discharge from ICU or day 28. Analysis is performed (i)at rest in supine position with bed at zero degrees of inclination (ii) during modified tilt (MTILT) and (iii) recovery from MTILT in supine position at zero degrees. In a subgroup of patients motor sympathetic nervous activity (MSNA) is recorded at day 1,2 and 7. MTILT consists in elevating head and trunk of patients at 60 degrees and lowering legs at 15 degree with a standard critical care bed. MSNA is recorded from the external peroneal nerve with microneurographic technique. | Other | All patients |
Primary outcome
Incidence of autonomic nervous system dysfunction in critical ill patients
Time frame: from day 1 to day 28
failure to change significantly HRV and baroreflex variables in response to MTILT.
4 secondary outcomes
to measure the occurrence of ANS failure in subgroups
Time frame: from day 1 to day 28
Length of stay in ICU and in Hospital
Time frame: 8 months
mortality
Time frame: 8 months
days free from mechanical ventilation
Time frame: 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2014.
- Background: PubMed 21658013Mazzeo AT, La Monaca E, Di Leo R, Vita G, Santamaria LB. Heart rate variability: a diagnostic and prognostic tool in anesthesia and intensive care. Acta Anaesthesiol Scand. 2011 Aug;55(7):797-811. doi: 10.1111/j.1399-6576.2011.02466.x. Epub 2011 Jun 9.
- Background: PubMed 17481504Morris JA Jr, Norris PR, Waitman LR, Ozdas A, Guillamondegui OD, Jenkins JM. Adrenal insufficiency, heart rate variability, and complex biologic systems: a study of 1,871 critically ill trauma patients. J Am Coll Surg. 2007 May;204(5):885-92; discussion 892-3. doi: 10.1016/j.jamcollsurg.2007.01.019. Epub 2007 Mar 23.
- Background: PubMed 18241783Schmidt H, Hoyer D, Wilhelm J, Soffker G, Heinroth K, Hottenrott K, Said SM, Buerke M, Muller-Werdan U, Werdan K. The alteration of autonomic function in multiple organ dysfunction syndrome. Crit Care Clin. 2008 Jan;24(1):149-63, ix. doi: 10.1016/j.ccc.2007.10.003.
- Background: PubMed 23275003Wieske L, Kiszer ER, Schultz MJ, Verhamme C, van Schaik IN, Horn J. Examination of cardiovascular and peripheral autonomic function in the ICU: a pilot study. J Neurol. 2013 Jun;260(6):1511-7. doi: 10.1007/s00415-012-6818-6. Epub 2012 Dec 30.
- Background: PubMed 2874900Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res. 1986 Aug;59(2):178-93. doi: 10.1161/01.res.59.2.178.
- Background: PubMed 9118511Pagani M, Montano N, Porta A, Malliani A, Abboud FM, Birkett C, Somers VK. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation. 1997 Mar 18;95(6):1441-8. doi: 10.1161/01.cir.95.6.1441.
- Background: PubMed 11045994Porta A, Baselli G, Rimoldi O, Malliani A, Pagani M. Assessing baroreflex gain from spontaneous variability in conscious dogs: role of causality and respiration. Am J Physiol Heart Circ Physiol. 2000 Nov;279(5):H2558-67. doi: 10.1152/ajpheart.2000.279.5.H2558.
- Background: PubMed 10694528Furlan R, Porta A, Costa F, Tank J, Baker L, Schiavi R, Robertson D, Malliani A, Mosqueda-Garcia R; New Collective Author. Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus. Circulation. 2000 Feb 29;101(8):886-92. doi: 10.1161/01.cir.101.8.886.
- Background: PubMed 10332107Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL; New Collective Author. Human responses to upright tilt: a window on central autonomic integration. J Physiol. 1999 Jun 1;517 ( Pt 2)(Pt 2):617-28. doi: 10.1111/j.1469-7793.1999.0617t.x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ferdinando Raimondi, Director study chair
Azienda Ospedaliera "L.Sacco"
Riccardo Colombo, Consultant principal investigator
Azienda Ospedaliera "L.Sacco"
Stefano Guzzetti, Director study director
Azienda Ospedaliera "L.Sacco"
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Gravitational sympathetic stimulus in people with Autonomic Nervous System Dysfunction in Critically Ill, run by ASST Fatebenefratelli Sacco at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Nov 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of autonomic nervous system dysfunction in critical ill patients (time frame: from day 1 to day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01930669, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2014.