Change in pulse transit time and pre eje

Journal of Clinical Monitoring and Computing (2007) DOI: 10.1007/s10877-007-9086-8 Ó Springer 2007 11 12 13 14 Gregory S H Chan1,2, Paul M Middleton1,3, Branko G Celler, PhD1, Lu Wang1 and Nigel H Lovell, PhD1,2,4 ABSTRACT Objective Traditional vital signs such as heart rate (HR) and blood pressure (BP) are often regarded as insensitive markers of mild to moderate blood loss The present study investigated the feasibility of using pulse transit time (PTT) to track variations in pre-ejection period (PEP) during progressive central hypovolaemia induced by head-up tilt and evaluated the potential of PTT as an early non-invasive indicator of blood loss Methods About 11 healthy subjects underwent graded head-up tilt from to 80° PTT and PEP were computed from the simultaneous measurement of electrocardiogram (ECG), finger photoplethysmographic pulse oximetry waveform (PPGPOW) and thoracic impedance plethysmogram (IPG) The response of PTT and PEP to tilt was compared with that of interbeat heart interval (RR) and BP Least-squares linear regression analysis was carried out on an intra-subject basis between PTT and PEP and between various physiological variables and sine of the tilt angle (which is associated with the decrease in central blood volume) and the correlation coefficients (r) were computed Results During graded tilt, PEP and PTT were strongly correlated in 10 out of 11 subjects (median r = 0.964) and had strong positive linear correlations with sine of the tilt angle (median r = 0.966 and 0.938 respectively) At a mild hypovolaemic state (20–30°), there was a significant increase in PTT and PEP compared with baseline (0°) but without a significant change in RR and BP Gradient analysis showed that PTT was more responsive to central volume loss than RR during mild hypovolaemia (0–20°) but not moderate hypovolaemia (50–80°) Conclusion PTT may reflect variation in PEP and central blood volume, and is potentially useful for early detection of non-hypotensive progressive central hypovolaemia Joint interpretation of PTT and RR trends or responses may help to characterize the extent of blood volume loss in critical care patients 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 RR EC TE D PR OO F Chan GSH, Middleton PM, Celler BG, Wang L, Lovell NH Change in pulse transit time and pre-ejection period during head-up tilt-induced progressive central hypovolaemia J Clin Monit Comput 2007 CO 10 CHANGE IN PULSE TRANSIT TIME AND PRE-EJECTION PERIOD DURING HEAD-UP TILT-INDUCED PROGRESSIVE CENTRAL HYPOVOLAEMIA UN 56 KEY WORDS pulse transit time (PTT), pulse transmission time, pre-ejection period, head-up tilt, hypovolaemia, blood loss 48 49 50 51 52 INTRODUCTION From the Biomedical Systems Laboratory, School of Electrical Engineering and Telecommunications, University of New South Wales, Sydney, NSW 2052, Australia; 2Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia; 3Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2031, Australia; 4National Information and Communications Technology Australia (NICTA), Eveleigh, NSW 1430, Australia Received 10 May 2007 Accepted for publication July 2007 Address correspondence to N H Lovell, Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia E-mail: N.Lovell@unsw.edu.au Early detection of internal bleeding has often been a difficult task for clinicians Vital sign monitors that are currently in use in emergency department (ED) or in emergency transport vehicles measure a range of physiological variables including heart rate (HR) and blood pressure (BP) but these variables are often regarded as insensitive markers of mild to moderate blood loss [1, 2] The decrease in central blood volume during early stage of blood loss typically triggers a baroreflex response that acts to maintain a perfusing BP despite a decline in stroke volume BP may not decrease considerably until about Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK 53 54 55 56 57 58 59 60 61 62 63 Journal of Clinical Monitoring and Computing 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 METHODS AND MATERIALS 150 Subject 151 About 11 healthy subjects (10 males and female, aged 18–44 years, mean age 30 years) were studied Prior to the experiment, subjects were requested to provide information about their physical condition and none reported any history of cardiovascular or respiratory disease Written informed consent was obtained from all participants, and the study was approved by the Human Research Ethics Advisory (HREA) Panel of the University of New South Wales 152 153 154 155 156 157 158 159 160 Measurement devices and systems 161 PPG-POW was measured from the tip of the right index finger using a reflection mode infrared finger probe 162 163 D PR OO F The purpose of the present study was to identify the change in PTT associated with the decline in central blood volume, similar to that which occurs during mild to moderate blood loss Graded head-up tilt was used as a model to simulate progressive central hypovolaemia [3–5, 18, 19] The sine of the tilt angle (sinh) is proportional to the hydrostatic effect of head-up tilting [20, 21], and a linear relationship has been found between sinh and the decrease in thoracic fluid content [22] Although graded head-up tilt is not truly equivalent to actual blood loss since the blood volume is merely re-distributed to the lower body under gravitational influence rather than actually lost from the circulatory system, it may at least simulate most of the cardiovascular responses to a progressive decline in central blood volume similar to that occurring during haemorrhage In the current study, the change in PTT and PEP at different levels of central blood volume induced by graded tilt was examined along with corresponding responses in interbeat heart interval (RR) and BP Intra-subject regression analysis was carried out (1) between PTT and PEP to determine how much PEP contributed to the PTT variations associated with change in central blood volume, and (2) between the different physiological variables and sinh to determine the association of the variables with central blood volume Moreover, the gradient of the variables with respect to tilt angle increment was computed to provide a measure of the directional change in the variable in response to a further decrease in central blood volume at a given volume status represented by the tilt angle A positive/negative gradient would indicate an increasing/decreasing trend in the variable as volume loss progressed CO RR EC TE 30% of total blood volume has been lost, by which time patients are at high risk of cardiovascular collapse as a result of haemorrhagic shock [1, 3–6] Delayed control of haemorrhage has been recognized as a major contributor to preventable trauma deaths and has often been related to delays in the assessment or diagnosis of haemorrhage [7, 8] There are potentially large benefits to the critical care clinician if small volume losses could be diagnosed early, accurately and reproducibly simply by the assessment of a physiological variable that can be conveniently derived from existing patient monitoring equipment Recently, a significant amount of research effort has been devoted to the pulse transit time or the pulse transmission time (PTT) [9, 10] PTT is typically measured as the time interval from the R-wave of the electrocardiogram (ECG) to a reference point on the systolic upstroke of a subsequent peripheral pulse wave It consists of two components: the pre-ejection period (PEP), which corresponds to the timing from the onset of ventricular depolarisation to the onset of ventricular ejection, and the vascular transit time (VTT), which defines the period for the arterial pulse wave to travel from the aortic valve to the peripheral arteries In particular, the PEP component of PTT is known to vary with cardiac preload [11–13] Recent studies have shown that respiratory variation in PTT/PEP could predict fluid responsiveness in patients [14, 15] From the perspective of clinical monitoring, PTT has the potential to become widely applied in patient care since its derivation only requires ECG and a peripheral pulse waveform, such as the finger photoplethysmographic pulse oximetry waveform (PPG-POW) which has been commonly used for the monitoring of arterial oxygen saturation (SpO2) Both ECG and PPGPOW are routinely measured by existing vital sign monitors, and their measurement is totally noninvasive and causes minimal discomfort to the patients By monitoring PTT in a continuous beat-by-beat manner, it may be possible to identify subtle change in the patientÕs cardiovascular status caused by small amounts of progressive blood loss over time Previous studies have identified the potential value of PTT in the detection of hypotension caused by central hypovolaemia [16, 17] Ahlstrom et al showed that PTT could track changes in systolic BP during simulated hypovolaemia with lower body negative pressure (LBNP) [16] A study of actual haemorrhage in dogs by Ochiai et al demonstrated that hypotension caused by acute blood loss could be potentially identified as a prolongation in PTT [17] However, these studies involved a high degree of central hypovolaemia which subsequently led to hypotension It is not clear whether PTT is also useful for detecting mild hypovolaemia in the absence of significant BP reduction UN 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK Chan et al.: PTT/PEP in progressive hypovolaemia 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 The subjects were advised not to eat for at least h prior to the study, with any meal to be free of alcohol and caffeine beverages The subjects were also asked not to undertake any intensive exercise within 12 h before the study All measurements were made in a quiet dimly lit room at an ambient temperature of approximately 24°C The subject initially rested in a supine position on the tilt table for a period of 20 minutes The subjectÕs feet were supported by a footboard, and straps were applied at the levels of waist and knees to stabilize the body during headup tilting Measurements were made at each of the following tilt angles in incremental order: 0, 10, 20, 30, 40, 50, 60 and 80° At each tilt angle, PPG-POW, ECG and thoracic IPG were simultaneously recorded for a period of 15 s, followed by a measurement of BP A 15 s measurement period is considered sufficient to encompass at least one respiratory cycle, allowing the influence of respiratory phase on the measurements to be minimized by averaging Once measurements at the current tilt angle were completed, the subject was tilted to the next angle After each tilt, and before the next phase of measurement commenced, a 1.5 adaptation period allowed the measured cardiovascular variables to settle to a stable level, which generally takes up to 30 s [24] Measurements were Signal processing and parameter extraction 219 F Measurement protocol 215 216 217 218 All signal processing and feature extraction were implemented in Matlab (the MathWorks Inc., Natick, USA) The R-wave peaks were detected from the ECG signal using a set of automatic programming routines involving lowpass filtering, differentiation, and threshold peak detection The processing of the PPG-POW and the AC component of the thoracic IPG involved four main stages: (1) Lowpass filtering—An 8th order Butterworth lowpass filter with a 3-dB point at 18 Hz was designed to remove high frequency noise Zero-phase filtering was implemented, which involved filtering the signal in both forward and backward directions, to eliminate phase distortion (2) Baseline removal—The baseline of the two signals was approximated by moving averaging For the PPG-POW, a s window (3-dB point at 0.23 Hz) was used, whereas for the thoracic IPG, a 1.5 s window (3-dB point at 0.3 Hz) was used The baseline component was subsequently subtracted from the respective signals (3) Differentiation— A 5-point digital differentiator was designed to differentiate the two signals to obtain the first derivative (d1), the second derivative (d2), and the third derivative (d3), namely d1PPG-POW, d2PPG-POW and d3PPG-POW for PPGPOW, and dZ/dt, d2Z/dt2 and d3Z/dt3 for thoracic IPG The high order derivatives were generally noisy and therefore were smoothed by moving averaging with a 31.3 ms window (3-dB point at 14 Hz) (4) Pulse detection—A threshold detection algorithm was implemented for detecting the systolic peaks from the derivatives of the two signals All the data traces were free of artefact and therefore artefact rejection was not necessary Several timing parameters were derived from ECG, PPG-POW, and thoracic IPG, including RR, PTT, PEP and VTT RR was computed as the time interval between successive R-wave peaks PTT was computed as the time interval between the R-wave peak and the arrival of the subsequent pulse in finger d1PPG-POW (see Figure 1) In the present study, d1PPG-POW was taken as the reference pulse signal for PTT measurement due to its close association with arterial inflow [25] The reference point chosen for PTT computation was the onset or foot of d1PPG-POW, which could be reliably detected from the systolic peaks in d3PPG-POW based on the second derivative method [26] PEP was computed as the time interval between Rwave peak and the onset of ventricular ejection detected from the subsequent thoracic dZ/dt pulse (see Figure 1) PR OO 190 made with the subject breathing spontaneously BP measurements and finger PPG-POW signals were acquired with the subjectÕs forearms supported by armrests maintained at close to the heart level D (ADInstruments, Sydney, Australia) ECG was acquired from the lead I configuration and amplified with a bioamplifier (ADInstruments, Sydney, Australia) The thoracic impedance plethysmogram (IPG) was acquired using the Tetrapolar High-Resolution Impedance Monitor, also known as the THRIM (UFI, Morro Bay, USA) The two Ag/AgCl electrodes for current injection were placed on the right clavicle and on the left leg respectively A constant sinusoidal alternating current of 50 kHz and 0.1 mA rms, which was not perceivable by the subjects, was applied between the two current injecting electrodes The two Ag/AgCl electrodes for the measurement of thoracic IPG were positioned over the sternum: one at the top of the sternum and another superior to the xiphoid process From the anatomical perspective, this electrode arrangement should produce a thoracic IPG which reflects the change in blood volume predominantly in the aorta and in the thoracic vessels [23] The signals were recorded and digitised at a sampling rate of 1000 Hz using the Powerlab data acquisition system (ADInstruments, Sydney, Australia) BP measurements, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP), were obtained using a clinically approved oscillometric BP device (Colin Co., Japan) from a cuff placed around the left arm over the brachial artery UN CO RR EC TE 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 Journal of Clinical Monitoring and Computing d1PPG−POW PTT 0.2 0.4 0.6 0.8 Time (s) RESULTS 303 The results are expressed as mean ± SE Overall, there was significant change in RR (p < 0.001), PTT (p < 0.001), PEP (p < 0.001), VTT (p < 0.001), DBP (p < 0.05), MAP (p < 0.05) and PP (p < 0.01) during tilting but no significant change in SBP (p > 0.05) Table shows the values of RR, PTT, PEP, VTT, SBP, DBP, MAP and PP at 304 305 306 307 308 309 TE Fig Detection of PEP, PTT and VTT from ECG (top), thoracic dZ/ dt (middle), and d1PPG-POW (bottom) PEP corresponds to the time interval from the R-wave peak (square) to the onset of ventricular ejection detected from thoracic dZ/dt (triangle), PTT corresponds to the time interval from the R-wave peak to the foot of the d1PPG-POW pulse (circle), and VTT corresponds to the time interval between the onset of ventricular ejection and the foot of the d1PPG-POW pulse PR OO VTT D Thoracic dZ/dt PEP 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 F ECG mean and standard error (SE) of all subject measurements at each tilt angle were calculated, and the mean ± SE was plotted against sinh The range and coefficient of variation of PTT and PEP were computed for and 80° Moreover, the gradient of the variable was calculated as the difference in the variable divided by the difference in sinh between successive tilt angles, to measure the directional change of the variable in response to a unit decrement in central blood volume The average gradients of the variable in three stages were computed: (1) 0–20° (mild hypovolaemia), (2) 20–50° (mild-to-moderate hypovolaemia), (3) 50–80° (moderate hypovolaemia) Nonparametric FriedmanÕs ANOVA test for repeated measures was used to determine whether any significant change occurred in the variable and its gradient during sequential tilting, and when significant change was detected, Wilcoxon signed rank test was performed post hoc with Bonferroni correction to test whether there was significant increase/decrease in the variable from baseline (0°) or in its gradient between the three stages Wilcoxon signed rank test with Bonferroni correction was also used to test whether there was a significant positive/negative gradient in each stage For all statistical tests, p < 0.05 was considered significant Leastsquares linear regression analysis was carried out between PTT and PEP, and between each variable and sinh The correlation coefficient (r) was computed The regression relationship was considered significant if p < 0.05 R-wave peak was used as the reference point to represent ventricular depolarisation due to the reliability of its detection [16, 17] The onset of ventricular ejection was identified from thoracic dZ/dt by locating the so-called B-point, which appeared as an incisura at the base of the rising edge of the large systolic wave in dZ/dt [27] and was detected using the derivatives [28] 273 Data analysis 274 275 The RR, PTT, PEP and VTT of a subject at a given tilt angle were averaged over the 15 s recording period The CO RR EC 266 267 268 269 270 271 272 Table Physiological variables at different tilt angles RR (ms) 10 20 30 40 50 60 80 1031 ± 17 1031 ± 30 998 ± 25 966 ± 32 929 ± 36* 881 ± 45* 847 ± 40** 797 ± 45** PTT (ms) PEP (ms) VTT (ms) SBP (mmHg) DBP (mmHg) MAP (mmHg) PP (mmHg) 190 ± 195 ± 202 ± 7* 204 ± 7* 208 ± 7* 212 ± 7* 211 ± 8* 215 ± 7** 109 ± 117 ± 6* 122 ± 7* 126 ± 6* 132 ± 7* 137 ± 6** 139 ± 7** 143 ± 7** 81 ± 78 ± 80 ± 78 ± 77 ± 75 ± 72 ± 3** 72 ± 104 ± 107 ± 106 ± 107 ± 106 ± 105 ± 105 ± 105 ± 60 ± 60 ± 58 ± 59 ± 58 ± 61 ± 61 ± 63 ± 75 ± 76 ± 75 ± 75 ± 75 ± 76 ± 78 ± 79 ± 44 ± 47 ± 47 ± 48 ± 47 ± 44 ± 43 ± 42 ± UN h (°) Results are presented as mean ± SE ** p < 0.01, * p < 0.05: significant increase/decrease from 0° (with Bonferroni correction made) Abbreviations: h = tilt angle Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK Chan et al.: PTT/PEP in progressive hypovolaemia 250 150 100 50 F 200 PR OO PTT, PEP, VTT (ms) PTT 0.2 0.4 PEP VTT 0.6 0.8 sinΘ D Fig PTT, PEP and VTT against sinh As sinh increases, PEP and PTT increase in a linear manner, while VTT decreases slightly significant decrease in gradient compared with 0–20° was identified in RR at both 20–50° and 50–80° The results of intra-subject regression analysis of PEP against PTT, and RR, PTT, PEP, VTT, SBP, DBP, MAP and PP against sinh are shown in Table The correlation between PEP and PTT was generally strong (median r = 0.964, range of r from 0.626 to 0.988), and 10 out of 11 subjects had positive and significant regression relationships (p < 0.05) The regression slope of PEP against PTT was significantly positive (1.18 ± 0.13) PEP had the strongest correlation with sinh (median r = 0.966), and the regression relationships were positive RR EC TE different tilt angles and any significant changes from baseline There was no significant change in RR from baseline at 10–30° but there was significant decrease at 40° and above PTT was significantly higher than baseline at 20° and above whereas PEP was significantly higher than baseline at 10° and above At 0°, PTT ranged from 152 to 228 ms with CV of 11%, whereas PEP ranged from 75 to 134 ms with CV of 16% At 80°, PTT ranged from 160 to 255 ms with CV of 11%, whereas PEP ranged from 98 to 174 ms with CV of 16% The percentage change in mean PTT and PEP between and 80° were 13 and 31% respectively There was no significant change in VTT from baseline except for a significant decrease at 60° No significant change from baseline was observed in SBP, DBP, MAP and PP In Figures 2–4, the mean ± SE of each variable is plotted against sinh As sinh increased, RR decreased with the rate of decrease tending to be greater at higher tilt angles PTT and PEP, on the other hand, increased linearly with sinh, while VTT decreased slightly The BP variables did not appear to change with sinh at low tilt angles, although there was a tendency for MAP and DBP to increase and for PP to decrease at high tilt angles Table shows the gradients of RR, PTT, PEP, VTT, SBP, DBP, MAP and PP at the three stages (0–20°, 20– 50° and 50–80°) and any significantly positive gradient (rising trend) or negative gradient (falling trend) A significantly negative gradient was identified in RR at 20– 50° and 50–80° and in PP at 20–50° A significantly positive gradient was identified in PTT at 0–20° and 20– 50°, in PEP at all three stages and in MAP at 50–80° Overall, there was a significant change in gradient in RR (p < 0.05) and DBP (p < 0.05) but not in other variables A CO 1100 800 SBP 100 90 RR BP (mmHg) 900 110 UN 1000 RR (ms) 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 80 MAP 70 DBP 60 50 PP 40 700 0 0.2 0.4 0.6 0.8 0.2 0.4 0.6 0.8 sinΘ sinΘ Fig RR against sinh As sinh increases, RR decreases with the rate of decrease tending to be greater at higher tilt angles Fig SBP, MAP, DBP and PP against sinh The BP variables not appear to change with sinh at low tilt angles although there is a tendency for MAP and DBP to increase and for PP to decrease at high tilt angles Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK 348 349 350 351 352 353 354 355 356 357 358 359 Journal of Clinical Monitoring and Computing Table Gradients of physiological variables at the three stages RR (ms) PTT (ms) PEP (ms) VTT (ms) 0–20 )98 + 49 20–50 )285 + 77** 50–80 )380 + 69** ## ## SBP (mmHg) DBP (mmHg) MAP (mmHg) PP (mmHg) 35 + 8** 38 + 9** )3 + 5+5 23 + 6** 35 + 4** )11 + )2 + 14 + 13 28 + 9* )14 + 12 + )5 + 6+3 10 + )2 + 2+3 16 + 6* F h (°) 10 + )8 + 2* )9 + PR OO Results are presented as mean ± SE ** p < 0.01, * p < 0.05: significantly positive/negative gradient (with Bonferroni correction made) p < 0.01, # p < 0.05: significant increase/decrease from 0–20° (with Bonferroni correction made) Abbreviations: h = tilt angle ## 377 378 379 380 381 DISCUSSION 382 D significantly negative ()8.8 ± 2.7 ms) The regression relationships between the BP variables and sinh varied considerably between subjects and did not reach statistical significance for most subjects, and the regression slopes were not significant The present study highlights the potential value of PTT as a sensitive early non-invasive marker of falling central blood volume Graded head-up tilt from to 80° has been used as a model to simulate the transition from mild to moderate central hypovolaemia, similar to that occurs in progressive blood loss An important new finding of the present study is that PTT can signal a drop in central blood volume relative to the normovolaemic state (0°) at a EC TE and significant in 10 out of 11 subjects The subject who had poor correlation between PEP and sinh (r = 0.417, p > 0.05) also had poor correlation between PEP and PTT (r = 0.626, p > 0.05) The regression slope of PEP against sinh was significantly positive (33.9 ± 4.4 ms) PTT showed a strong correlation with sinh (median r = 0.938), and the regression relationships were positive and significant in out of 11 subjects The regression slope of PTT against sinh was significantly positive (25.0 ± 3.0 ms) RR also showed a strong correlation with sinh (median r = )0.927), and the regression relationships were negative and significant in out of 11 subjects The regression slope of RR against sinh was significantly negative ()245 ± 47 ms) VTT showed a moderate negative correlation with sinh (median r = )0.665), but the regression relationships were negative and significant in only out of 11 subjects The regression slope of VTT against sinh was RR Table Correlation coefficients from intra-subject regression analysis PEP-PTT RR-h PTT-h PEP-h VTT-h SBP-h DBP-h MAP-h PP-h 10 11 Med r Max r Min r Mean m ±SE m 0.969* 0.964* 0.931* 0.981* 0.982* 0.717* 0.965* 0.988* 0.813* 0.626 0.867* 0.964 0.988 0.626 1.18* ±0.13 )0.952* )0.514 )0.618 )0.941* )0.960* )0.855* )0.927* )0.988* )0.944* )0.927* )0.774* )0.927 )0.514 )0.988 )245* ±47 0.829* 0.982* 0.957* 0.980* 0.996* 0.890* 0.938* 0.988* 0.627 0.515 0.622 0.938 0.996 0.515 25.0* ±3.5 0.922* 0.978* 0.966* 0.966* 0.978* 0.899* 0.987* 0.990* 0.843* 0.417 0.899* 0.966 0.990 0.417 33.9* ±4.4 )0.937* )0.584 )0.790* )0.612 )0.753* )0.365 0.065 )0.958* )0.804* 0.473 )0.665 )0.665 0.473 )0.958 )8.8* ±2.7 0.186 )0.015 0.521 )0.819* )0.030 0.708* )0.263 )0.051 )0.708* )0.213 0.730* )0.030 0.730 )0.819 )0.16 ±2.12 )0.181 )0.249 0.912* )0.716* 0.257 0.559 0.201 0.846* )0.455 )0.273 0.947* 0.201 0.947 )0.716 2.49 ±2.32 0.306 )0.176 0.741* )0.682 )0.126 0.708* 0.308 0.703 0.338 0.272 0.622 0.308 0.741 )0.682 2.92 ±1.66 0.275 0.155 )0.101 )0.244 )0.161 0.128 )0.461 )0.570 )0.295 )0.081 )0.898* )0.161 0.275 )0.898 )2.65 ±1.26 CO Subject UN 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 * p < 0.05: significant Abbreviations: PEP-PTT = PEP against PTT, RR-h = RR against sine of the tilt angle etc The table displays the correlation coefficients of the intra-subject regressions, with the last five rows corresponding to the median, maximum and minimum of the subjectsÕ correlation coefficients, and the mean and standard error of the regression slopes Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK 383 384 385 386 387 388 389 390 Chan et al.: PTT/PEP in progressive hypovolaemia D PR OO F demonstrated by the considerable overlap in the ranges of PTT comparing the normovolaemic state (0°) with the most hypovolaemic state (80°) and the high inter-subject CV (11%) relative to the percentage difference (13%) between the two states Alternatively, the trend or gradient of PTT may be useful for identifying patients who are progressively losing blood, since dynamic volume decrease may result in a rising trend in PTT over time In the current study, three different stages of physiological response to central volume loss have been identified: Stage (0–20°): This stage simulated mild central hypovolaemia A rising trend was observed in PTT/PEP as preload decreased No significant falling trend was observed in RR, probably because small decrement in central blood volume at a mild hypovolaemic state was not sufficient to trigger noticeable baroreflex response Stage (20–50°): This stage simulated mild-to-moderate central hypovolaemia PTT/PEP continued to show a rising trend as preload decreased A falling trend was also observed in RR, which could be attributed mostly to vagal withdrawal and also to sympathetic activation The more negative RR gradient in this stage compared with stage might result from augmented baroreflex responsiveness as central blood volume decreased [30] Stage (50–80°): This stage simulated moderate central hypovolaemia A significant rising trend was not observed in PTT even though PEP was increasing with preload reduction, and this suggested that the decline in VTT might have offset the rise in PEP The decline in VTT indicated an increase in pulse wave velocity (PWV) induced by sympathetic activation, which might result from a rise in MAP/DBP causing a passive increase in arterial stiffness or from an increase in myocardial contractility [31, 32] PEP, despite continuing to increase, showed a weaker rising trend in this stage, possibly because the lengthening effect of preload reduction was opposed by the shortening effect of sympathetic activation [12, 13] A falling trend in RR continued in this stage as a result of the combined influence of vagal withdrawal and sympathetic activation with further reduction in central blood volume Based on the observed physiological response to the three stages of simulated hypovolaemia, it is clear that rising trend in PTT can be a useful marker for progressive volume loss in stages and (mild and mild-to-moderate hypovolaemia), but not when the patient has entered stage (moderate hypovolaemia) In stage 3, sympathetic activation is believed to cause variation in VTT which reduces the ability of PTT to follow changes in PEP The shortcoming of PTT can be mitigated, however, by also considering RR, which tends to fall sharply as a result of an enhanced sympathetic tone The present study has demonstrated that the joint interpretation of PTT and RR trends may offer promising CO RR EC TE much early stage than RR and BP A significant rise in PTT occurred at 20° tilt whereas a significant fall in RR only occurred at 40° tilt and above, while BP did not show any significant change from baseline at all tilt angles The change in PTT during mild to moderate central hypovolaemia has been shown to reflect predominantly the change in PEP, and this finding is in agreement with the study by Newlin which revealed considerable contribution of PEP to PTT variation [29] A significantly positive linear correlation between PTT and PEP has been observed in 10 out of 11 subjects The non-significant correlation observed in one subject was partly attributed to the lack of PEP response to tilting as indicated by the poor correlation between PEP and sinh, but generally, the correlation coefficient between PTT and PEP was high (median r = 0.964), justifying the potential use of PTT to monitor PEP variations during mild change in volume status Progressive prolongation of PEP/PTT during graded head-up tilt is believed to reflect a decline in stroke volume caused by the reduction of cardiac preload (or end diastolic volume) as a result of orthostatic volume shift from the central venous pool to the lower body [11] During head-up tilt, the hydrostatic effect of tilting is proportional to sinh which reflects the body axis component of gravitational pull exerted on the blood volume inside the body [20, 21] As demonstrated by the present study, PEP and PTT had strong positive correlation (r > 0.8) with sinh in most subjects and the overall regression slopes were significantly positive These findings are consistent with the observed linear relationship between sinh and the decrease in thoracic fluid content during graded head-up tilt [22] and suggest that PEP and PTT may reflect proportional change in central blood volume or preload A new way of studying the haemodynamic effect of progressive hypovolaemia using gradient/trend analysis of PTT and RR has been presented in this study that may permit better characterization of the different stages of blood loss From the perspective of clinical application, we propose that the changing trends in PTT and RR may be more useful than their absolute values for identifying and distinguishing between different phases of progressive blood loss It is well recognized that trends in physiological variables, both with evolving pathology and with resuscitative measures, are very useful diagnostically and prognostically in acute illness Although PTT may be augmented in hypovolaemia compared with normovolaemia, in a real life situation critical care clinicians often need to diagnose blood loss without prior knowledge of the patientsÕ pre-haemorrhage physiological variables It seems not possible to use absolute values of PTT to identify patients with low central blood volume because of the high degree of inter-subject variability, as UN 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 Journal of Clinical Monitoring and Computing possibility of not only detecting the presence, but also estimating the extent of progressive blood loss For example, a change in the patientÕs status from rising PTT and unchanged RR to unchanged/falling PTT and falling RR may indicate the transition from mild hypovolaemia to moderate hypovolaemia 503 PTT/PEP and BP 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 Although an increase in afterload (represented by MAP/ DBP) due to peripheral vasoconstriction may also lead to an increase in PEP [33], it was unlikely to be the major cause of the tilt-induced change in PEP and PTT because MAP/DBP did not have a significant linear relationship with sinh The lack of concomitant BP change with mild decrease in central blood volume induced by head-up tilt has been reported elsewhere [34–37], and this finding supports the concept of insensitivity of BP to small volume loss [1] It is known that in phase I of haemorrhage (loss of up to 750 ml or 15% of total blood volume), sympathetic activation would help to maintain a stable BP despite a drop in stroke volume, and only until blood loss reaches a critical level (30–40% of total blood volume), a decompensatory phase II commences during which BP and HR fall dramatically [3–5] In contrast to previous studies which utilized PTT as a surrogate marker of BP change for detecting hypovolaemia-induced hypotension [16, 17], the present study demonstrates that PTT may in fact be a more robust indicator of mild volume loss than BP itself and may signal an early stage of hypovolaemia well before the phase II hypotension occurs The theoretical basis for the use of PTT as a surrogate marker of BP was initially suggested to be the potential negative correlation between VTT/PWV and BP [38] but the relationship between PTT and BP can be significantly influenced by the variation in PEP which may oppose the change in VTT [17, 29, 39] The results of this study have provided further evidence that PTT and PEP can change in a disassociated way from VTT and BP during mild to moderate central hypovolaemia 535 Head-up tilt as a model of progressive hypovolaemia 536 537 538 539 540 541 542 543 544 545 In this study, progressive central hypovolaemia was induced in healthy awake subjects by incremental head-up tilt from to 80° The use of head-up tilt as a model to simulate the major haemodynamic response to haemorrhage in humans has been documented elsewhere [3–5, 18, 19] Although tilt-induced central hypovolaemia is not identical to actual blood loss since the blood volume is merely re-distributed to the lower body rather than actually lost from the circulatory system, the initial cardiovascular response to haemorrhage is essentially the same as that elicited by a reduction in central blood volume, e.g by head-up tilt or by lower body negative pressure (LBNP) [4–6, 19] About 24° head-up tilt produces a similar cardiovascular response to 15 mmHg LBNP [36], which approximates mild haemorrhage (loss of 400–550 ml or 10% of total blood volume) [6], while 60° head-up tilt produces a similar central cardiovascular response to 20–40 mmHg LBNP [37], which approximates moderate haemorrhage (loss of 550–1000 ml or 10–20% of total blood volume) [6] However, a limitation of using head-up tilt as a model of blood loss is that the regional blood volume changes and the associated vascular responses induced by gravitational fluid shift to the lower body can be different from that in actual haemorrhage [37, 40] Nonetheless, head-up tilt may still be regarded as an acceptable model to simulate most of the cardiovascular effect of falling central blood volume that occurs in blood loss 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 Comparison with actual haemorrhage in anaesthetized dogs 564 Since the present findings are based on a simulated model of haemorrhage, whether the results are applicable to an actual blood loss situation remains to be investigated Kubitz et al studied variation in PEP and cardiac preload during acute haemorrhage in pigs, but concluded that PEP was not sensitive to the change in intravascular volume status [41] Ochiai et al showed that acute blood loss led to significant prolongation in VTT and PTT, yet with no significant change in PEP [17] We suggest that one reason for the lack of PEP change in these haemorrhage studies may be due to the magnitude of blood loss being severe given the presence of hypotension It was noted in the present study that PEP showed a weaker rising trend in stage (50)80°) compared with stage and (0–50°), which suggests that PEP may be less sensitive to volume change as the degree of hypovolaemia becomes more severe, most likely due to the opposite effect of preload reduction and sympathetic activation Another possible reason for the difference may be the effect of experimental procedure on the physiologic response of haemorrhaged animals, including the method of blood withdrawal and the induction of anaesthesia which may have confounding effects on the cardiovascular response to volume loss [42, 43] For example, the use of isoflurane in the study by Ochiai et al could lead to vasodilatation and might subsequently influence the PEP/PTT response to haemorrhage 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 Technical aspects of PTT/PEP derivation 591 The ability of PTT to monitor PEP variation may depend on which part of the peripheral pulse waveform is used as a reference point for PTT measurement In the present study, 592 593 594 UN CO RR EC TE D PR OO F 497 498 499 500 501 502 Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK Chan et al.: PTT/PEP in progressive hypovolaemia 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 The ability of PTT to identity early stages of hypovolaemia has a potentially enormous benefit to clinical practice, in particular for those cases associated with covert haemorrhage into body cavities that are not easily recognizable at the beginning Delayed control of abdominal, pelvic or intrathoracic haemorrhage has been recognized as a major contributor of preventable trauma deaths and is often caused by delays in the assessment or diagnosis of haemorrhage [7, 8] Notably, it would be of great interest if such events could be detected as early as possible based on information that could be obtained from existing patient monitoring devices Although PTT may not be as good as PEP for detecting preload variation due to the confounding effect of VTT, it can be easily computed from simultaneous measurements of ECG and finger pulse oximetry, both of which have been routine patient monitoring techniques for some years The measurements of ECG and finger PPG-POW are totally F Clinical application of PTT PR OO 628 noninvasive, cause minimal discomfort to the patients, and can be obtained continuously in a beat-to-beat manner which may permit the early detection of small physiological perturbations It would certainly be advantageous to critical care clinicians if these two routine measurements can provide information relevant to the diagnosis of blood loss in addition to their conventional use for HR and SpO2 monitoring Apart from detecting progressive blood loss, the response pattern of PTT/PEP to graded tilt at different volume status may also have direct relevance towards the use of tilt test in the clinical assessment of hypovolaemia and fluid responsiveness Due to a lack of response to volume challenge in some patients who are suspected to be hypovolaemic, the test for fluid responsiveness has often been considered an important initial therapeutic question [46] In clinical practice, one method to test for fluid responsiveness is to measure the haemodynamic change by first tilting the patient to the reverse Trendelenburg position (30° head-up tilt) to induce relative depletion of central blood volume then to the Trendelenburg position (30° head-down tilt) to simulate volume expansion [47] Ideally, the change in stroke volume or cardiac output during the manoeuvre would define fluid responsiveness, but in cases where stroke volume or cardiac output measurements are not available or not preferred due to their invasive nature, non-invasive indices such as PTT/PEP may be useful alternatives Previous studies have demonstrated the potential value of respiratory fluctuation in PTT/PEP in predicting fluid responsiveness [14, 15] The current study has further demonstrated the possibility of using PTT/PEP for assessing fluid responsiveness by studying their dynamic change during tilt manoeuvres, although more clinical studies are required to validate this For the PTT technique to be applied clinically, several issues need to be addressed in future investigations; firstly, it is unclear what the optimal duration is for the reliable detection of an increasing/decreasing trend of PTT/RR associated with blood loss Certainly, the analysis period has to be sufficiently long since both PTT and RR exhibit respiratory fluctuations as well as other spontaneous low frequency oscillations [14, 39, 48] that may confound the genuine trend related to physiological perturbations Secondly, there is a need to identify patient groups whose PEP/PTT may have limited responsiveness to a change in preload, such as those who suffer from heart failure [11] Thirdly, the PTT measurement may be influenced by the contact force with the sensor [49], the peripheral temperature [50] and the limb position [51] Whether these factors would affect the applicability of PTT in the monitoring of critical care patients remains to be investigated D the first derivative of the finger PPG-POW (d1PPGPOW) was used as the reference pulse waveform since it is considered to be closely related to peripheral arterial flow [25] The foot of d1PPG-POW was used as the reference point for pulse arrival, in order to eliminate the potential contribution of the rising time of systolic upstroke on PTT, so that the PTT measurement would more closely reflect the variation in PEP In fact, it is possible that sympathetic activation during haemorrhage may induce a change in the systolic rising time that opposes the prolongation of PEP caused by preload reduction For PEP measurements, the present study used thoracic IPG to identify the onset of ventricular ejection The thoracic dZ/dt pulse waveform has been regarded as a measure of intrathoracic blood volume change and experimental evidence tended to suggest a major role played by systolic blood volume expansion in the ascending aorta [23, 44], although the precise anatomic site of its onset (B-point) remains speculative Nevertheless, it has been demonstrated that B-point occurred synchronously with the first heart sound which marks the onset of ventricular contraction [27] and the use of Bpoint to estimate PEP has been validated by comparison with the standard technique based on carotid pulse and phonocardiogram [45] Comparing PEP measurements in our study with Stafford et al [11], the differences between the mean PEP at equivalent tilt angles were actually quite small (the differences were ms at 0°, ms at 10°, )2 ms at 20 and 30°, and ms at 60°), despite the difference in methodology used for PEP computation The close agreement between the PEP measurements in our study and in Stafford et al provides us with further reassurance that the thoracic IPG-based technique is reliable UN CO RR EC TE 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 Journal : 10877 Dispatch : 18-7-2007 Pages : 11 Article No : 9086 MS Code : JOCM-07-90 h LE h CP h TYPESET h DISK 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 Journal of Clinical Monitoring and Computing In conclusion, this study has shown that PTT may reflect variation in PEP and is potentially useful for early detection of non-hypotensive progressive central hypovolaemia Joint interpretation of PTT and RR trends or responses may help to characterize the extent of blood volume loss Further work is required to evaluate the applicability of PTT in the examination of critical care patients who may be suffering from haemorrhage 708 709 710 We would like to thank Dr Ross Odell for his valuable advice on data analysis REFERENCES CO RR EC TE American College of Surgeons Shock In: ATLS Instructors Manual Chicago: First Impressions; 1993 p 75–94 McGee S, Abernethy WB III, Simel DL The rational clinical examination Is this patient hypovolemic? 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