Abstract
Introduction
The quantification of blood loss in a severe trauma patient allows prognostic quantification and the engagement of adapted therapeutic means. The Advanced Trauma Life Support classification of hemorrhagic shock, based in part on hemodynamic parameters, could be improved. The search for reproducible and non-invasive parameters closely correlated with blood depletion is a necessity. An experimental model of controlled hemorrhagic shock allowed us to obtain hemodynamic and echocardiographic measurements during controlled blood spoliation. The primary aim was to demonstrate the correlation between the Shock Index (SI) and blood depletion volume (BDV) during the hemorrhagic phase of an experimental model of controlled hemorrhagic shock in piglets. The secondary aim was to study the correlations between blood pressure (BP) values and BDV, SI and cardiac output (CO), and pulse pressure (PP) and stroke volume during the same phase.
Methods
We analyzed data from 66 anesthetized and ventilated piglets that underwent blood spoliation at 2 mL.kg −1 .min −1 until a mean arterial pressure (MAP) of 40 mmHg was achieved. During this bleeding phase, hemodynamic and echocardiographic measurements were performed regularly.
Results
The correlation coefficient between the SI and BDV was 0.70 (CI 95%, [0.64; 0.75]; p < 0.01), whereas between MAP and BDV, the correlation coefficient was −0.47 (CI 95%, [−0.55; −0.38]; p < 0.01). Correlation coefficient between SI and CO and between PP and stroke volume were − 0.45 (CI 95%, [−0.53; −0.37], p < 0.01) and 0.62 (CI 95%, [0.56; 0.67]; p < 0.01), respectively.
Conclusions
In a controlled hemorrhagic shock model in piglets, the correlation between SI and BDV seemed strong.
1
Introduction
Among traumatic deaths, hemorrhagic shock (HS) represents the leading cause of mortality [ , ]. Time is a major prognostic factor in the management of a trauma patient in HS [ ], especially in the pre-hospital setting [ ]. Approximately 85% of deaths related to HS occur within six hours after hospital admission [ ], which imposes the need to develop rapid and efficient management strategies. Damage control resuscitation [ , ], based on early fluid infusion and blood product transfusion with a moderate mean arterial pressure (MAP) objective [ , ], and damage control surgery, based on rapid surgical management of bleeding [ ], have improved the prognoses of patients in hemorrhagic shock [ ]. Compensatory physiological mechanisms may initially lead to an underestimation of the severity of a hemorrhage, for which quantification of the volume of blood lost is difficult [ ].
The correlation between hemodynamic parameters and blood depletion volume (BDV) needs to be explored to determine simple and reproducible criteria that can predict HS in severe trauma patients (STP). Heart rate (HR) and systolic blood pressure (SBP) are simple and reproducible tools to access and use but not sufficient when used alone; this has led to a controversial Advanced Trauma Life Support (ATLS) classification of HS [ ]. Pulse pressure variations (PPVs) are moderately correlated with BDV [ ]. The Shock Index (SI), defined by the HR/SBP ratio, has been evaluated as a risk factor for massive hemorrhage in severe trauma [ , ]. An increased SI in the management of severe trauma would be a poor prognostic factor [ ] and a predictive factor for massive transfusion [ ], suggesting an association between this hemodynamic parameter and the extent of hemorrhage.
Our hypothesis was that SI is correlated with BDV. The main aim of our study was to show the correlation between SI and BDV in an experimental model of controlled HS in anesthetized and ventilated piglets.
2
Methods
2.1
Materials
We performed an analysis based on data from four series of experiments performed between 2018 and 2022. The protocol used in this model of controlled HS in piglets was approved (CEEALR-12013 and 9341–2,021,012,709,128,801). The manipulations were performed in a certified laboratory. This animal-based study was conducted according to European Directive 2010/63/EC, which supervises the protection of animals used for scientific purposes.
Our primary objective was to show the correlation between SI and BDV in an experimental model of controlled HS in piglets. The secondary objective was to show the correlations between different blood pressure (BP) values and BDV, SI and cardiac output (CO), and pulse pressure (PP) and stroke volume (SV) in this same experimental model.
2.2
Animal preparation
A total of 66 piglets participated in these experimental studies with this model of HS. All animals were prepared according to a previously published and validated protocol [ ]. Premedication was performed by intramuscular injection of ketamine 10 mg.kg −1 , atropine 0.05 mg.kg −1 , and midazolam 10 mg.kg −1 . Anesthetic induction was performed by a bolus of propofol (4 mg.kg −1 ) combined with curarization by cisatracurium (0.25 mg.kg −1 ) and maintained with propofol 8 mg.kg −1 .h −1 . After orotracheal intubation or surgical tracheostomy, the piglets were ventilated with an inspired oxygen fraction of 21%, a tidal volume of 6 or 8 mL.kg −1 , and a positive end-expiratory pressure of 5 cmH 2 O. The animals were then conditioned with echo-guided placement of a 7 French triple-lumen central venous line through the internal jugular vein to the right atrium, permitting measurement of central venous pressure and allowing for injection of cold water boluses for transpulmonary thermodilution. One femoral artery was catheterized with a 5 French arterial catheter with an integrated thermistor (PiCCO®Plus; Pulsion Medical Systems, Munich, Germany) that allowed continuous BP monitoring. Finally, the femoral vein was also cannulated by an 8.5 French catheter (Arrow®; Arrow International, Inc., Cleveland, OH, USA) to perform blood withdrawal or fluid filling. These different invasive measurement tools allowed continuous monitoring of BP and HR in particular.
2.3
Experimental protocol and measurement times
As the objective of this study was to assess the evolution of SI in hemorrhage, we only describe the standardized depletion phase of the experimentation. The experiment started at T0 by recording reference hemodynamic data for each animal, including HR and BP values, as well as biological and echocardiographic data. Blood depletion was then initiated via a femoral venous catheter at a rate of 2 mL.kg −1 .min −1 until a mean arterial pressure (MAP) of 40 mmHg was obtained, which defined T1. The same hemodynamic and echocardiographic measurements were performed every 5 mL.kg −1 of blood withdrawal, defining T0a, T0b, T0c, etc. At T1, the hemodynamic, biological, and echocardiographic data were measured ( Fig. 1 ).
The SV was calculated by the invasive measurement of CO multiplied by HR. PPVs were calculated based on invasive measurements of SBP and diastolic blood pressure (DBP). Ultrasound measurements were performed by a physician with expertise in echocardiography according to the recommendations of the American Society of Echocardiography [ ] with a Venue R2.6 (Venue R2.6, GE Medical Systems, Milwaukee, WI, USA), Versana Balance (Versana Balance, GE Medical Systems, Milwaukee, WI, USA), or Vivid S70 (Vivid S70, GE Medical Systems, Milwaukee, WI) device. Measurement of the sub-aortic velocity–time integral (VTI) was performed in a five-cavity apical view with pulsed Doppler. The four-cavity apical view was preferred to measure the E’ wave at the lateral mitral annulus using tissue Doppler. Measurements of the minimum and maximum values of the diameter of the inferior vena cava (IVC) were performed in a substernal view. The distensibility of the IVC (dIVC) was calculated according to the formula dIVC = (IVCmax – IVCmin) / ((IVCmax + IVCmin) / 2).
2.4
Statistical analysis
As no studies of SI in this model of HS were available, no sample size calculation was performed. Quantitative data were expressed as mean and standard deviation. Qualitative data were expressed as frequencies with percentages. An analysis of variance (ANOVA) was performed to compare the quantitative data between each time point of the experiment. Pearson’s correlation coefficients were calculated to assess the relationship between the judgment criteria and blood depletion. The correlation coefficient was interpreted as negligible [0.00; 0.10], weak [0.10; 0.39], moderate [0.40; 0.69], strong [0.70; 0.89], or very strong [0.90; 1.0] [ ]. The significance level was set at 5% for all tests. Statistical analysis was performed in R (version 4.0.2, 2017, R Foundation for Statistical Computing, Vienna, Austria).
3
Results
3.1
Animals and measurement times
Of the 66 piglets included in this data analysis, 52 (79%) were female. The number of piglets included per year was 18 (27%), 17 (26%), 18 (27%), and 13 (20%) in 2018, 2020, 2021, and 2022, respectively. The mean weight was 31 ± 4 kg. A total of 428 hemodynamic measurements were performed at different times during the hemorrhagic phase of the protocol. The quantitative hemodynamic and echocardiographic data are described in Table 1 . The mean BDV of all experiments was 18.10 ± 10.59 mL.kg −1 .
| Variable | T0 | T0a | T0b | T0c | T0d | T0e | T0f | T0g | T0h | T1 | p |
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR (bpm) | 99 ± 23 | 103 ± 24 | 107 ± 28 | 117 ± 33 | 130 ± 34 | 142 ± 39 | 148 ± 37 | 181 ± 30 | 206 ± 24 | 146 ± 51 | <0.01 |
| SBP (mmHg) | 97 ± 13 | 83 ± 15 | 73 ± 15 | 73 ± 13 | 69 ± 14 | 68 ± 15 | 66 ± 14 | 64 ± 12 | 61 ± 13 | 49 ± 6 | <0.01 |
| MAP (mmHg) | 77 ± 12 | 67 ± 12 | 59 ± 12 | 58 ± 11 | 56 ± 11 | 54 ± 11 | 53 ± 12 | 52 ± 10 | 48 ± 9 | 38 ± 3 | <0.01 |
| DBP (mmHg) | 63 ± 10 | 54 ± 10 | 48 ± 11 | 47 ± 9 | 46 ± 10 | 45 ± 9 | 45 ± 10 | 44 ± 9 | 39 ± 7 | 32 ± 4 | <0.01 |
| SI (bpm/mmHg) | 1.04 ± 0.33 | 1.27 ± 0.39 | 1.52 ± 0.53 | 1.64 ± 0.47 | 1.92 ± 0.57 | 2.17 ± 0.67 | 2.24 ± 0.63 | 2.77 ± 0.43 | 3.34 ± 0.38 | 3.04 ± 1.08 | <0.01 |
| PP (mmHg) | 34 ± 8 | 29 ± 8 | 25 ± 8 | 25 ± 6 | 24 ± 8 | 23 ± 8 | 21 ± 5 | 20 ± 5 | 22 ± 7 | 17 ± 5 | <0.01 |
| VPP (%) | 18.3 ± 6.7 | 20.8 ± 6.6 | 23.8 ± 7.6 | 25.6 ± 8.5 | 27.9 ± 8.7 | 27.7 ± 7.5 | 27.4 ± 6.2 | 33.0 ± 3.7 | 31.5 ± 3.1 | 29.1 ± 8.1 | <0.01 |
| E’ wave (cm.s −1 ) | 11.24 ± 3.54 | 9.61 ± 2.99 | 8.76 ± 2.48 | 7.75 ± 2.47 | 7.06 ± 2.96 | 6.34 ± 2.43 | 4.90 ± 2.14 | 4.09 ± 1.74 | 5.90 ± 1.79 | 6.04 ± 2.42 | <0.01 |
| VTI (cm) | 13.43 ± 3.09 | 11.68 ± 2.69 | 10.90 ± 2.20 | 10.06 ± 2.18 | 9.50 ± 2.67 | 8.89 ± 1.89 | 8.53 ± 2.46 | 8.18 ± 3.44 | 9.92 ± 5.39 | 8.60 ± 2.41 | <0.01 |
| dIVC (%) | 0.64 ± 0.56 | 0.72 ± 0.59 | 0.87 ± 0.75 | 0.90 ± 0.65 | 1.08 ± 0.79 | 1.27 ± 0.80 | 1.15 ± 0.83 | 1.15 ± 0.94 | 0.71 ± 0.90 | 0.74 ± 0.67 | 0.05 |
| SV (mL) | 34.32 ± 9.33 | 29.17 ± 8.33 | 25.37 ± 6.93 | 23.01 ± 6.38 | 18.86 ± 5.44 | 16.61 ± 5.81 | 14.80 ± 4.61 | 10.33 ± 2.43 | 8.49 ± 2.17 | 14.0 ± 7.0 | <0.01 |
| CO (L.min −1 ) | 3.29 ± 0.90 | 2.94 ± 0.88 | 2.64 ± 0.73 | 2.57 ± 0.63 | 2.35 ± 0.61 | 2.25 ± 0.67 | 2.17 ± 0.70 | 1.88 ± 0.56 | 1.75 ± 0.45 | 1.74 ± 0.41 | <0.01 |
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