Arterial and Plethysmographic Waveform Analysis in Anesthetized Patients with Hypovolemia

• ❖ Respiratory variations in arterial pressure and plethysmographic waveforms correlate with major blood loss, although the effect of mild blood loss is less well known

• ❖ In 33 surgical patients undergoing controlled blood withdrawal for hemodilution, arterial and pulse oximetry waveform changes with respiration were reliable measures of mild blood loss

ESTIMATION of intravascular volume is one of the basic clinical tasks of the anesthesiologist. Although the limitations of assessing the changes in heart rate (HR) and blood pressure (BP) during blood loss are well known, the clinical diagnosis of hypovolemia is still often based on those two parameters.1,2There is a high level of suspicion of hypovolemia in patients with decreased BP and/or tachycardia, but diagnosing hypovolemia when those two signs are within normal limits might be difficult.

Respiratory-induced arterial BP and plethysmographic waveform changes in mechanically ventilated patients have been repeatedly shown to be sensitive indicators of hypovolemia 3–6as well as sensitive predictors of cardiac output response to fluid infusion7,8and other types of preload changes, such as passive leg raising or changing in airway pressure.9–14Those dynamic variables have been shown to be better predictors of cardiac output response to fluid loading than the traditional static variables, such as central venous pressure or pulmonary artery occlusion pressure, or even data from transesophageal echocardiography.15,16Respiratory-induced variations in arterial and plethysmographic waveforms and stroke volume have become acceptable physiologic signs of cardiac output responsiveness to fluid loading,17and some monitors are already equipped with online automatic measurement of these parameters.

Despite the growing popularity of respiratory-induced arterial and plethysmographic waveform parameters, only few studies have evaluated waveform variations after protocol-driven mild blood volume reduction. These studies evaluated the waveform signal in response to only one step of 10% of the estimated decrease in circulating blood volume (ECBV), and their results have shown significant changes in waveform variables, although the reliability of these changes in estimating less extensive, mild blood loss was not studied.3,5,6Waveform changes resulting from smaller amounts of blood loss and the degree of reliability by blood volume changes of less than 10% of the ECBV have never been evaluated. However, during the last 2 decades, some authors have questioned the relevance of those parameters in nonhypotensive patients.18 

We hypothesized that changes in arterial and plethysmographic respiratory-induced waveform variables reliably reflect the degree of mild blood loss in anesthetized and otherwise hemodynamically stable patients. To test our hypothesis, we evaluated the accuracy of the different respiratory-induced arterial and pulse oximetry plethysmographic waveform variables during mild hypovolemia.

Patients scheduled for elective hip arthroplasty, suprapubic prostatectomy, or nephrectomy and who had a plan for autologus hemodilution were eligible for the study. Exclusion criteria included patients with a hemoglobin concentration less than 13.0 g/dl, a creatinine concentration more than 1.5 mg/dl, with coronary or cerebrovascular event during the past 6 months, or whose cardiac rhythm was other than a normal sinus rhythm. After obtaining institutional review board (Carmel Medical Center, Haifa, Israel) approval for this study and signed written informed consent from the patients, all study participants received standard anesthesia care. Patients treated chronically with β-adrenergic antagonists received regular doses of their medication and 10 mg diazepam orally on the morning of the surgery. Angiotensin-converting enzyme inhibitors were skipped on the day of surgery.

Each patient received 7 ml/kg lactated Ringer's solution during the induction of general anesthesia by 1.5 μg/kg fentanyl and 2.0–2.5 mg/kg propofol. Tracheal intubation was facilitated with 0.6 mg/kg rocuronium, positive pressure ventilation was applied (tidal volume 8 ml/kg of ideal body weight), and anesthesia was maintained with nitrous oxide/oxygen (1:1) + isoflurane (end-expiratory concentration 0.4%) throughout the period of blood autodonation. The frequency of mechanical ventilation was adjusted to remain between 8 and 12 to keep end-tidal carbon dioxide at 33–37 mmHg.

Blood was withdrawn by steps of 2% of ECBV up to 20% of ECBV (10 steps), which was calculated by the following formula: ([1486 × body surface area]− 825) + (1578 × body surface area) for men and ([1.06 × age]+[822 × body surface area]) + (1395 × body surface area) for women.19Blood was collected in a citrate phosphate dextrose adenine bag. The criteria for blood withdrawal discontinuation were as follows: a decrease in systolic BP by more than 20% from the values observed immediately before start of blood withdrawal, a systolic BP less than 80 mmHg, or the occurrence of dysrhythmia. Each step of blood withdrawal with concomitant recording of waveforms took about 3 min, with no pauses between steps. Blood volume was replaced with an equal volume of colloid solution after the completion of blood withdrawal (6% hydroxyethyl starch 200/0.5; Fresenius Kabi, Deutchland GmbH, Germany). Autologous blood was retransfused to the patient at the end of the surgical procedure.

Arterial and plethysmographic (pulse oximetry) waveforms were recorded with a Datex-Ohmeda AS-3 (Datex, Helsinki, Finland) recorder and analyzed off-line at baseline and after each step of blood withdrawal. A pulse oximeter probe was placed on the patient's index finger and wrapped with a towel to prevent interference from outside light. The pulse oximeter of the monitor was set for the manual size mode and the signal was kept at the same scale throughout the study period. Arterial and plethysmographic waveforms were recorded using the printer module of the monitor. Paper recordings were scanned at a resolution of 300 dpi. The computer images were measured using the format shape function of Word (Office 2003; Microsoft Co., Redmond, WA) with the lock-to-grid function disabled. All the measured points were verified by two independent researchers.

The systolic pressure variations (SPV), dUp, dDown, and pulse pressure variations (PPV) were analyzed using standard methods (fig. 1).4,9The plethysmographic waveform variations (PWV) of the pulse oximetry signal were calculated as follows: the difference between the maximal and minimal plethysmographic signals divided by the amplitude of the plethysmographic signal during apnea (fig. 1).6The delta pulse oximetry plethysmographic (dPOP) waveform amplitude was calculated as follows: (POP^max− POP^min)/([POP^max+ POP^min]/2) (fig. 1).20Only patients who tolerated all 10 steps (i.e ., 20% of circulating blood volume) of the blood withdrawal protocol were included in this analysis.

Values are presented as mean ± SD unless otherwise stated. Comparisons of variables before and after blood withdrawal were performed with the paired t  test. The relationship between hemodynamic variables and the steps of blood withdrawal was analyzed by a linear mixed model.21A mixed model takes into account the within-patient correlation and includes all available data for each patient. Each step of ECBV reduction was taken as a fixed categorical variable (with 11 levels) to estimate differences from baseline. Compound symmetry structure was assumed for the covariance matrix of the repeated measures. Applying the Bonferroni correction, a P  value less than 0.005 was considered significant for comparisons with the baseline value, as 10 differences were tested.22The F  value of the mixed model test was used to compare the magnitude of the relationship between hemodynamic variables during all stages of blood withdrawal.

The mean coefficient of variation (SD/mean) was used to compare the variability of the parameters. Correlations between SPV and PPV, PWV, and dPOP for each step of blood withdrawal were calculated using the Pearson correlation coefficient.

To test the slope difference of two periods of ECBV reduction, that is, steps 0–5 and steps 6–10, a second mixed model21was performed. The model includes time as a fixed continuous variable and as an indicator variable for period (first five steps = 0 and the last five steps = 1), and interaction (that estimates the difference in slopes of the two periods).

The Pearson correlation coefficient of each waveform variable to the stages of blood withdrawal in every patient was calculated to estimate the supplemental value of each variable. Statistical calculations were performed with the SPSS 15.0 (SPSS Inc., Chicago, IL).

Total 109 patients were recruited in the study, and 33 of them tolerated withdrawal of 20% of estimated blood volume without decrease in systolic BP below 80 mmHg and or by more than 20% of baseline value. The demographic data of the 33 study participants who tolerated gradual 20% blood withdrawal without significant hypotension are presented in table 1. Because of the small number of patients with concomitant diseases and receiving medications chronically, we did not perform quantitative analysis. The entire procedure, from the initiation of recording at baseline until the recording after 20% of ECBV withdrawal, took 25–30 min. As a result of blood withdrawal, the hemoglobin concentration decreased from 13.7 ± 1.2 g/dl to 13.0 ± 1.3 g/dl (P < 0.0001) before replacement with colloid. Peak airway pressure did not change during the study period; it was 20.7 ± 4.6 cm H²O at the beginning and 20.6 ± 4.6 cm H²O at the end of blood withdrawal.

Although the increase in HR became significant after 18% of ECBV withdrawal, the changes were small and clinically insignificant (fig. 2). The HR increased only by 4% after a 20% reduction of ECBV. Similarly, the changes in systolic and mean arterial BPs were mild, although the decrease was already significant after a 6% withdrawal of ECBV (fig. 2). The maximal reduction of 11% in systolic BP was observed after withdrawal of 20% of ECBV. The decrease in arterial pulse pressure was also gradual and reached statistical significance after 6% ECBV withdrawal (fig. 2). However, the magnitude of reduction was only 16% after a 20% withdrawal of ECBV (table 2). As measured by the coefficient of variation, the changes of HR and arterial pressures were consistent during all stages of the study (table 2).

The values of plethysmographic waveform variables, PWV and dPOP, increased gradually during the steps of blood withdrawal. The PWV value became significantly different from baseline after a 6% withdrawal of ECBV, and the dPOP value became significantly different after an 8% withdrawal of ECBV, with the changes of both variables reaching more than 100% from baseline values after a 20% withdrawal of ECBV (table 2, fig. 3). The relationship (measured by the F  value of a mixed model) between these two variables and the steps of blood withdrawal was stronger, and the coefficient of variation (variability of variable) was lower in PWV compared with that of dPOP (table 2).

The SPV and PPV became significantly different from baseline values after a 4% reduction of the ECBV during gradual blood withdrawal, and the dDown became significantly different from baseline values after a 6% reduction of the ECBV during gradual blood withdrawal (figs. 3, 4). The changes were more than 80% for each of those variables after a 20% withdrawal of the ECBV. The dUp component of the SPV did not change significantly, although the absolute value became negative in five patients, indicating considerable hypovolemia. The degree of changes in the SPV and PPV during the first five steps of blood withdrawal was less prominent compared with the ensuing steps of blood volume reduction (P = 0.006 for the SPV and P = 0.002 for the PPV). The dDown did not show any difference in the pattern of changes between the early and later stages of blood withdrawal.

The strength of the relationship (F  value) between the SPV and the step of blood withdrawal was stronger and the coefficient of variation was lower compared with those of the PPV, signifying that changes in the SPV were more closely dependent on the step of blood withdrawal and that there was less variability between individual subjects (table 2).

The Pearson coefficient of correlation between waveform variables and stages of blood withdrawal in each patient was used to estimate the supplemental value of the parameters. The correlations with the steps of blood withdrawal were not significant in two patients for SPV, in four patients for PPV, in five for PWV, and in 11 for dPOP (fig. 5and table 3). Three of the four patients with nonsignificant correlations of their PPV with steps of blood withdrawal had a significant correlation between their SPV and steps of blood withdrawal, although only one patient had no correlation of all waveform variables with steps of blood withdrawal.

Correlations between the SPV and PPV, PWV, and dPOP increased with deeper hypovolemia. Both plethysmographic variables correlated well with the corresponding arterial waveforms variables (i.e ., PWV with SPV and dPOP with PPV), and those correlations were greater at deeper stages of blood withdrawal (fig. 6and table 4).

Our hypothesis was that arterial and pulse oximeter plethysmographic waveforms are reliable indicators of hypovolemia in otherwise hemodynamically stable patients. The findings of the study that supported this hypothesis are follows: (1) reduction of even 4% of ECBV causes significant changes in respiratory-induced arterial waveform variables in otherwise hemodynamically stable patients; (2) respiratory-induced plethysmographic waveform signals follow arterial waveform changes with some delay and correlate accurately with the arterial BP waveforms at more advanced stages of blood loss; (3) respiratory-induced arterial waveform changes are more prominent during more extensive stages of hypovolemia than during early stages; and (4) SPV is the most reliable hemodynamic variable during graded hypovolemia.

The respiratory-induced arterial waveforms variables, such as SPV, dDown, and PPV, have repeatedly been shown to be sensitive predictors of cardiac output response to volume loading and other factors that affect venous return.7,8,10,12,23Arterial waveform variables have been used by several authors as guides for intraoperative fluid management.24,25However, those data are difficult to extrapolate for the purpose of diagnosing mild hypovolemia. This is the first study to evaluate the clinically relevant reliability of both respiratory-induced arterial and plethysmographic waveforms variations during gradually developing hypovolemia without arterial hypotension.

Our study simulates a clinically important situation in which substantial blood loss occurs without considerable changes in BP and HR (an only 11% change of systolic BP and a < 10% change in HR and mean BP). The early and consistent increase in values of waveform variables during blood withdrawal strongly supports the idea that these parameters are reliable indicators of mild hypovolemia in otherwise hemodynamically stable patients.

In our study group, SPV correlated better with blood volume reduction than PPV and had a smaller variability between patients throughout the study compared with other variables. These results are different from the previous studies by Michard et al .,26who found PPV to be a more sensitive and specific predictor of cardiac output changes after an increase in preload. There are several explanations for this discrepancy. We used a gradual multistep approach to reduce blood volume in contrast to the one-step increase in the preload that had been used in that and most of the previous studies.7,8,14,16,23,27In addition, they estimated cardiac response to volume expansion by an arbitrary threshold of cardiac output response, usually 10–15%, which probably affected the results.7,8,14,23,26,27Our data support the notion that SPV is at least reliable and even more consistent than PPV in reflecting hypovolemia and lend credence to the contention that it is easier to observe until automatic determination will become widely available.28 

The supplemental effect of different waveform variables is clearly evident in our data. By analyzing only their PPV, the diagnosis of hypovolemia could have been missed in four of the 33 patients in our group, whereas the additional measurement of SPV would have decreased the number of missed diagnoses to one. Although some waveform variables had more prominent changes than the SPV (fig. 4), SPV is more reliable by being more consistent during all stages of blood withdrawal.

Arterial waveforms changed more dramatically during ECBV withdrawal of 12–20% compared with 2–10%. There are at least two possible explanations for such a difference. Stroke volume is more sensitive to changes in preload when operating on the steep portion of the Frank–Starling curve; a similar decrease in preload results in a larger decrease in stroke volume that is reflected in higher variability in arterial systolic and pulse pressure, as well as in the plethysmographic waveform signal. An additional explanation for nonlinear changes in stroke volume could be a more effective recruitment of blood volume during the early stages of hypovolemia by mobilization of blood from an “unstressed” volume within the venous system that exists in normovolemic subjects, mostly in the splanchnic venous system.29It is reasonable to speculate that compensation from the venous system occurs to a greater extent at early stages of hypovolemia than at later ones when unstressed volume is already decreased.

Unlike the arterial signal that can be accurately measured, the plethysmographic pulse oximetry signal is not standardized, and, in addition, it is processed and filtered in different ways by different manufacturers.30,31The use of PWV to assess changes in blood volume, similar to arterial waveform variations, was first mentioned more than 2 decades ago.32Since then several studies have described different methods of analyzing the pulse oximetry plethysmographic signal.6,20,33–38In our current as well as previous studies, we used normalized plethysmographic AS signals (pulsatile) during apnea as reference points to calculate respiratory-induced PWV. We also measured respiratory dPOP that has also been used in several recent studies.20,36–38Contrary to previous studies that found the plethysmographic signal to be similar to the arterial waveform signal, we found some discrepancy between them. We observed low correlations of both the PWV and the dPOP with the arterial waveform variables at baseline and during early stages of blood withdrawal; these correlations significantly improved at more advanced stages of hypovolemia. This is in agreement with recent data that demonstrated a discrepancy between arterial and plethysmographic signals observed in an intensive care unit.39In this study, the plethysmographic variables showed a similar relationship with arterial waveforms, and significant improvement was seen in the correlation between them at more extensive stages of blood withdrawal (fig. 6). The difference between the PWV and the dPOP at early stages of hypovolemia and the significantly greater inconsistency between the dPOP and the PWV compared with the arterial waveform signals supports the need for an accurate evaluation of each new variable generated from pulse oximetry plethysmographic signals before introduction of the technique into wide clinical use.28 

There are several limitations to this study. The selection of patients with mild hypovolemia was based on an arbitrary threshold of systolic BP = 80 mmHg or within 20% of baseline. These two threshold limits were not prospectively evaluated, although they are frequently used in clinical practice as safety limits.40The volume of withdrawn blood could not be precisely equal to the 20% of real blood volume because the actual blood volume was not measured but rather calculated by a formula.19Despite these limitations, we believe that we have described a reasonable approximation of a human model of mild gradual hypovolemia that lasts for less than 30 min.

In conclusion, respiratory-induced arterial waveform changes are reliable indicators of small degrees of blood loss in otherwise hemodynamically stable anesthetized and mechanically ventilated patients. The SPV was the most reliable variable for estimating blood loss. The respiratory-induced plethysmographic waveforms accurately follow changes in arterial waveforms at more advanced stages of blood withdrawal.

The authors thank Esther Eshkol, M.A., Medical and Scientific Copyeditor, Tel Aviv, Israel, for her editorial assistance.