Transplanted-like Heart in Critical Ill Patients

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.

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.

To measure the autonomic nervous system activity elicited by a gravitational sympathetic stimulus in critically ill

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.

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

We measure length of stay in ICU and in hospital of patients without ANS dysfunction, with ANS dysfunction and with ANS failure

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)

We measure days free from mechanical ventilation among patients without ANS dysfunction, with ANS dysfunction and with ANS failure

First, we take the HRV and baroreflex variables' changes collected at day 1 of ICU stay in the first 50 patients. We set two cut-off values: (i)below 25th and (ii) below 10th percentiles. We define ANS dysfunction the presence of at least 1 HRV variable OR 1 baroreflex variable respectively below the first cut-off value (i), otherwise we define ANS failure the presence of at least 1 HRV variable OR 1 baroreflex variable below the second cut-off value (ii). Second, we prospectively test these cut-off values in the remaining 100 patients.

Inclusion Criteria: 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 Exclusion Criteria: 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

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