Cardioventilatory Coupling in Critically Ill Patients
Condition: Critically Ill
MeSH terms: Critical Illness
Study type: Interventional

Summary: 
      This study measures the cardioventilatory coupling in critically ill patients during
      mechanical ventilation in controlled mode (pressure controlled) and in patient-driven mode
      (pressure support and neurally adjusted ventilatory assist).
    

Detailed description: 
      Intrathoracic pressure oscillations due to positive pressure ventilation induce cyclic
      modifications of activity of the pulmonary vascular receptors and cardiac mechanoceptors.
      These effects changes the autonomic nervous system modulation with modification of both
      sympathetic and vagal activity.

      Cardio-ventilatory interaction recently has been studied through the heart rate variability
      in critically ill mechanical ventilated patients. The analysis of the power spectrum density
      provides information about the power (the variance of beat-to-beat interval) is distributed
      as frequencies' function. Healthy spontaneously breathing subjects show a cyclic inspiratory
      increase and expiratory decrease of heart rate, and 'phase coupling' between heart beats and
      respiration (causing heart beats to occur at constant phases of the respiratory cycle),
      commonly known as cardioventilatory coupling. These phenomena originate from a complex
      interplay of several mechanisms including central drive, feedback from arterial
      baroreceptors, feedback from thoracic and lung stretch receptors, and non-neural mechanisms
      intrinsic to the heart, which are not fully understood. Although the physiological importance
      of respiratory sinus arrhythmia and cardioventilatory coupling have not been elucidated,
      several authors suggested that they might improve ventilation/perfusion matching through a
      redistribution of heart beats (and consequently of perfusion) within the respiratory cycle,
      with beneficial effects on gas exchange. Furthermore, decreased respiratory sinus arrhythmia
      amplitude has been used as an indicator of impaired autonomic control and of poor clinical
      outcome, also during mechanical ventilation.It has been shown that during controlled
      mechanical ventilation the respiratory sinus arrhythmia amplitude is considerably reduced and
      the cardioventilatory coupling generally abolished. Theoretically, mechanical ventilation
      modes that assist the respiratory pump upon triggering by the patient, such as pressure
      support ventilation (PSV) might maintain higher respiratory sinus arrhythmia levels through
      centrally-originated phasic vagal modulation compared to controlled mechanical ventilation.
      In addition, mechanical ventilation with breath-by-breath variable tidal volumes, so-called
      'variable ventilation', could better preserve respiratory sinus arrhythmia and
      cardioventilatory coupling, and this might play a role in the improved arterial oxygenation
      found in different models of acute lung injury, although with variable results, when
      comparing variable and conventional mechanical ventilation. In anesthetized experimental
      animals the cardioventilatory coupling was more preserved during pressure assisted
      ventilation than pressure controlled ventilation. If these findings could be present in the
      humans is yet unknown. Furthermore, it has been demonstrated that some new methodologies of
      assisted ventilation, such as the neurally adjusted ventilatory assist (NAVA), increase the
      breath-to-breath variability and tidal volume variability, but their effects on
      cardioventilatory coupling are not understood.

      The study aims to measure the heart rate variability, the respiratory rate variability and
      the cardioventilatory coupling in critically ill patients during mechanical ventilation both
      in controlled mode (pressure controlled) and in assisted mode (pressure support ventilation
      and NAVA).

      Methods enrolled patients are connected to a S/5 ICU monitor (GE, Helsinki, Finland) and are
      mechanically ventilated with a Servo-I ventilator (Maquet, Germany) provided with
      diaphragmatic electrical activity module (EAdi, Maquet, Germany). A nasogastric 16-Fr EAdi
      catheter is positioned in all patients. A sequence of three consecutive study phases of
      different mechanical ventilation modes (PCV, PSV, and NAVA) is started. The sequence of
      ventilatory modes is randomized for every patient. After a 10 min acclimation period for each
      study phase, electrocardiographic, arterial pressure and ventilatory waves are collected for
      consecutive 30 min to a laptop pc via S/5 Collect (GE, Helsinki, Finland) and NAVA Tracker
      (Maquet, Germany) software for Windows.

      Heart rate variability analysis Linear analysis Sequences of 300 consecutives heart beats are
      selected inside each experimental phase. The mean and the variance of heart period are
      expressed in msec and msec^2 respectively. Autoregressive spectral density is factorized into
      components each of them characterized by a central frequency. A spectral component is labeled
      as LF if its central frequency is between 0.04 and 0.15 Hz, while it is classified as HF if
      its central frequency is between 0.15 and 0.5 Hz. The HF power is considered to represent
      respiration-driven vagal modulation of heart rate. To rule out the effect of changes of total
      power spectrum densities on LF and HF components, spectral values are also expressed in
      normalized units (NU). Normalization consisted in dividing the power of a given spectral
      component by the total power minus the power below 0.04 Hz (Very Low Frequency [VLF] spectral
      component), and multiplying the ratio by 100. The ratio of the LF power to the HF (LF/HF) is
      considered an indicator of the balance between sympathetic and vagal modulation directed to
      the heart.

      Nonlinear analysis Non-linear analysis was conducted by means of symbolic analysis. The
      symbolic analysis is conducted on the same sequences of 300 consecutive heart beats that are
      used for the autoregressive analysis. The whole range of the R-to-R interval into each series
      is uniformly divided in 6 slices (symbols) and pattern of 3 consecutive heart beat intervals
      were considered. Thus each sequence of 300 heart beats had its own R-to-R range and 298
      consecutive triplets of symbols. The Shannon entropy of the distribution of the patterns is
      calculated to provide a quantification of the complexity of the pattern distribution. All
      triplets of symbols are grouped into 3 possible patterns of variation: (i) no variation (0V,
      all 3 symbols were equal), (ii) 1 variation (1V, 2 consequent symbols were equal and the
      remaining symbol was different), (iii) patterns with 2 variations (2V, all symbols were
      different from the previous one). Previously, the percentage of 0V patterns was found to
      increase (and 2V decrease) in response to sympathetic stimuli, whereas 2V patterns increased
      (and 0V decreased) in response to vagal stimuli. The percentage of the patterns 0V and 2V was
      calculated, and the 0V/2V ratio was calculated to estimate the balance between sympathetic
      and vagal modulation.

      Cardioventilatory coupling analysis Phase synchronization method for quantification of
      coupling between weakly coupled self-sustained oscillators (here heart and ventilator) will
      be implemented. The idea behind is that a good ventilatory mode should produce
      cardio-respiratory coordination indistinguishable from that observed in healthy subject
      during spontaneous breathing at the same frequency and amplitude. Phase synchronization
      technique is complemented with joint symbolic analysis and cross-conditional entropy
      assessing of cardio-respiratory coupling in terms of degree of repeatability of coordination
      schemes between heart rate signal and ventilation. These approaches have the main advantages
      that they are less sensitive to non-stationarities and they are capable of capturing
      nonlinear couplings over shorter data sequences.

      Sample size given a heart rate variability total variance equal to 1000 msec^2, to detect a
      difference of 300 msec^2 (with a standard deviation of 200 msec^2) between the study phases
      with an alpha error=0.05, power=80%, effect size=0.4, 22 patients will be recruited.

      The normal distribution is checked with Kolmogorov-Smirnov test. Two tails Student t test for
      dependent or independent sample as needed, or Wilcoxon- U test in case of not normal
      distribution are employed. Repeated measures are analyzed with one way analysis of variance
      (ANOVA) followed by post-hoc Bonferroni's test.
    

Intervention name(s): Three different mechanical ventilation modes
Intervention type(s): Procedure
Intervention description(s): patients are randomly assigned to every arm. Baseline is the period immediatly before the study phase. The study phase is the sequence of three consecutive trials of different modes of mechanical ventilation. Every trial lasts 30 min plus 10 min of acclimation.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science
Keywords: mechanical ventilation; autonomic nervous system; heart rate variability; cardioventilatory coupling