Numerous studies1,2 have investigated the accuracy of hemoglobin (Hb) and Hct concentrations in assessing acute hemorrhage. These clinical studies propose them as potential indicators of acute anemia despite the logical presumption that their concentrations should remain unchanged post blood loss. To verify the model from the previous 4 prospective studies that were evaluated retrospectively, an internal control to demonstrate that the canine hemorrhagic shock model was appropriate, as defined by significant hypotension, hypovolemia, and anemia, was validated. The Wigger model has already been established as a valid model. Complementing these conventional metrics, point-of-care lactate and base deficit evaluations offer added insights into hemorrhage severity and tissue hypoperfusion.2 However, it is impossible to prospectively study human trauma victims with various strategies without having animal validation and not using standard-of-care treatments.3
Confirming whether or not Hb, Hct, lactate concentration, and base deficit reflect the degree of hemorrhage could be pivotal in directing resuscitation fluid management strategies, ensuring more personalized and efficacious interventions for patients in need.3,4 Since point-of-care devices offer rapid and accurate Hb measurements in the field, utilizing acute Hb changes may aid in therapy guidance.3,4 Our hypothesis is that there is a difference between initial and final Hb/Hct before and after hemorrhage across splenectomized canine hemorrhagic shock models. A secondary hypothesis is that there are no changes in lactate concentration or base deficit before and after acute hemorrhage.
Methods
One hundred twenty prospectively designed, randomized shock and resuscitation experiments on mixed-breed dogs were published previously, each experiment corresponding to a dog, to evaluate the hypothesis that Hb, Hct, lactate, and base deficit changes may reflect the severity of hemorrhage over time.5–8 Approval to study these dogs was obtained by the University of California-Davis IACUC. These studies were also done in compliance with the Guide to the Care of Laboratory Animals. This research review has been conducted in full compliance with the Animal Research: Reporting of In Vivo Experiments guidelines 2.0, ensuring the highest standards of reporting and methodological rigor in animal research.
Dogs were anesthetized and maintained with a balanced anesthesia protocol in order to account for and minimize any possible hemodynamic effects that could affect the values.5 In order to withdraw blood, determine systemic arterial pressures, and administer drugs and fluids, catheters were placed into the dogs’ lateral saphenous veins and both femoral arteries, and a pulmonary artery occlusion catheter and cardiac output monitor using the thermodilution technique was placed via the jugular vein and floated into position by the use of pressure wave forms.
Arterial blood was collected for arterial blood gases in heparinized syringes and immediately placed on ice prior to testing in an iSTAT monitor (Abbot Laboratories). All other blood samples for testing were arterial blood and stored refrigerated in a citrate-phosphate-dextrose tube until laboratory assessments were performed.
In all 4 original studies, all animals underwent the same anesthetic procedure:
The dogs were premedicated with oxymorphone (0.02 mg/kg, IM) and atropine (0.02 mg/kg, IM) followed by induction of anesthesia with propofol (2 ± 4 mg/kg, IV) and diazepam (0.5 mg/kg, IV), endotracheally intubated, and connected to a small animal anesthesia circuit. Anesthesia was maintained with isoflurane in 100% oxygen (end-tidal concentration of isoflurane, 0.8 ± 1.2%) and an infusion of fentanyl at a rate of 0.7 µg/kg/min that followed an initial bolus of fentanyl (10 µg/kg, IV) or an infusion of sufentanil at a rate of 0.04 µg/kg/min that followed an initial bolus of sufentanil (2 µg/kg, IV). The animals were mechanically ventilated with an anesthesia ventilator using tidal volumes of 12 ± 15 mL/kg and a respiratory rate of 9 ± 11 breaths/min. Ventilation was subsequently adjusted to ensure a PaCO2 in the range of 35 ± 45 mm Hg (4.6 ± 6.0 kPa).
Blood was withdrawn to a fixed mean arterial pressure (MAP) of 50 mm Hg and then maintained at that level for 60 minutes by slowly withdrawing more blood if necessary. The total amounts of blood withdrawn are reported in each study.
The canine spleen has a role of sequestering RBCs, which will be released into circulation during sympathetic stimulation as is the case during hypovolemia, and therefore all canines were surgically splenectomized.5–8 A splenectomy was performed after anesthetizing the dog, with open laparotomy, ligating the splenic artery and vein first prior to manipulation of the spleen to minimize the confounding factor of splenic release of RBCs into the circulation. Once the abdomen was closed, catheters were placed, and baseline measurements were performed.
Heart rate, mean arterial blood pressure, central venous pressure, pulmonary artery occlusion pressure, and cardiac output were additional values that were extracted. Various blood samples were intermittently collected from the femoral artery and right atrium and from arterial, mixed venous, and mesenteric venous blood.
Blood samples were then immediately sealed and stored on ice. A Nova Co-Oximeter (Nova Biomedical Corp) was used to measure total Hb, and Hct was calculated after centrifuging the blood sample in a capillary tube. All values were documented. Each laboratory machine was quality controlled daily as per the manufacturer’s standard operating procedure.
In the current study, the only data that was collected happened before any resuscitation strategies were performed from the original prospective studies. Data were generated during prior published studies and extracted from the database of the authors specifically to evaluate the hypothesis that Hb and Hct changes as well as lactate and base deficit.5–8 Data of interest were pooled from multiple prospectively designed canine hemorrhage shock and resuscitation experiments to evaluate the hypothesis that Hb, Hct, lactate, and base deficit changes may reflect the severity of hemorrhage over time and subsequently interpolate for therapeutic correction of acute anemia versus hypovolemia.
To evaluate the changes in Hct and Hb pre- and posthemorrhage, we used a complete case analysis approach. Data from 107 dogs were included in the analysis for summary pre- (N = 107) and posthemorrhage (N = 103) data. One hundred three dogs had complete data (4 dogs were missing posthemorrhage data) from both pre- and postsampling and were included in comparing pre- and postvalues and correlations. Although we had a total of 120 verified animals/dogs/experiments, there were some experiments that had data for both Hb and Hct, whereas others had data for only 1 of these measures because in some cases, complete data could not be recorded through the completion of resuscitation, leading to a decrease in sample size from pre- to posthemorrhage (eg, N pre/post = 107/103 for Hb and107/103 for Hct). As a result, all available values from these experiments were included in summarizing the pre- and postdata, but in the analysis comparing pre- and postvalues or potential correlations between measures, only animals with complete data were utilized (13 dogs did not have both Hct and Hb data and were excluded).
To evaluate the changes in blood pressure pre- and posthemorrhage, the following criteria were used to include and exclude experiments: out of 120 dog experiments, 34 were able to be statistically evaluated because these were the only studies5–8 that had full documentation recordings for blood pressure and heart variables from prehemorrhage through posthemorrhage.
The rationale behind this selection was that animals that were able to withstand the full experiment with resuscitation serve as better examples of human clinical comparisons. The animals that did not survive the protocol were excluded from the analysis. The authors removed nonsurviving experiments because we believe that our model is so severe that it may overcompensate for applicability to humans. For example, humans have been studied in cases where blood was not an option and found to survive Hg levels of 2 to 3 g/dL.9 Dogs may have translocation of gut bacteria in early shock and therefore not survive.8 The study protocol utilized in this evaluation is graphically described in Table 1. In the original 4 prospective studies, animals were euthanized after the resuscitation had been completed and studied.5–8
Original prospective study protocols.
| Characteristics | Reference #5 | Reference #6 | Reference #7 | Reference #8 |
|---|---|---|---|---|
| Sample size (male:female ratio) | n = 12 (5:7) | n = 24 (17:7) | n = 12 (8:4) | n = 19 (9:10) |
| Fasting (overnight) | Overnight | Overnight | Overnight | Overnight |
| Premedication | Oxymorphone, atropine | Oxymorphone, atropine | Oxymorphone, atropine | Oxymorphone, atropine |
| Anesthesia | Propofol, diazepam, isoflurane, fentanyl | Propofol, diazepam, isoflurane, sufentanil | Propofol, diazepam, isoflurane, fentanyl | Propofol, diazepam, isoflurane, fentanyl |
| Catheterization (saphenous vein and femoral arteries, pulmonary artery catheter [Swan Ganz Catheter; Edwards Lifesciences]) | Yes | Yes | Yes | Yes |
| PCO2 | 35–45 mm Hg | 35–45 mm Hg | 35–45 mm Hg | 35–45 mm Hg |
| Temperature (rectal) | 37–39 °C | 38–39 °C | 38–39 °C | 38–39 °C |
All experiments received lactated Ringer solution at 10 mL/kg/h during the laparotomy for splenectomy and then when abdomen closed, changed to 5 mL/kg/h until posthemorrhage up to the moment of baseline measurements and then stopped.
The first part of the study was to validate whether or not the model could be used retrospectively from previously published prospective studies. Once done, it was then possible to query the database and evaluate the research question. In a subset analysis, data from 60 dogs were extracted to compare baseline heart rate and MAP to posthemorrhagic values in a Wigger model of hemorrhagic shock. This was done by withdrawing set amounts of blood and maintaining MAP at a steady, hypotensive value of 50 mm Hg.
Study variables (Hct, Hb, lactate, etc) were summarized during the baseline and posthemorrhage periods using means and SDs. We formally compared the changes using the paired-samples t test along with 95% CIs. We also constructed line plots to better visualize the changes at the animal level (Figures 1 and 2). Prior to analysis, the normality assumption was assessed visually using quantile-quantile plots and histograms. Statistical analyses were performed using SPSS, version 29 (IBM Corp), and P values < .05 were considered statistically significant.
Hemoglobin (Hb) totals before (pre) and after (post) hemorrhage laboratory value testing were plotted for each animal as a separate line.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.08.0217
Hematocrit percentages before (pre) and after (post) hemorrhage laboratory value testing were plotted for each animal as a separate line. The following references were utilized for normals in dogs and listed as upper and lower reference ranges: Thrall MA, Weiser G, Allison RW, Campbell TW. Veterinary Hematology and Clinical Chemistry. John Wiley & Sons; 2012. Tvedten H, Weiss DJ. Hematology of dogs and cats. In: Weiss DJ, Wardrop KJ, eds. Schalm’s Veterinary Hematology. 6th ed. Wiley-Blackwell; 2012:799–819.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.24.08.0217
Results
Data were collected from 120 dogs.5–8 Baseline study variables were not different between dogs nor were there significant changes posthemorrhage (Table 2). Baseline study variables were not different between the groups of dogs between different studies. Baseline characteristics across the groups of dogs appeared generally comparable, with no notable differences observed for key variables due to similarities in protocols and other baseline measures between studies (Table 2).
Heart rate (HR) and arterial blood pressure (ABP) variables.
| Variables | Pre | Post | Difference (95% CI) | P value | n |
|---|---|---|---|---|---|
| HR (min−1) | 92.4 (23.1) | 199.4 (33.0) | 106.9 (98.4 to 115.4) | < .001 | 86 |
| ABP (mm Hg) | — | — | — | — | |
| Systolic | 135.6 (18.8) | 79.1 (19.5) | −56.5 (−61.6 to 51.3) | < .001 | 86 |
| Diastolic | 74.7 (13.1) | 33.4 (10.6) | −41.3 (−44.3 to 38.3) | < .001 | 86 |
| Mean | 90.7 (12.4) | 47.8 (11.8) | −42.9 (−46.2 to 39.5) | < .001 | 86 |
Values presented as mean (SD).
P values and 95% CIs were generated from the paired-samples t test.
As expected in a Wigger hemorrhage model, heart rate posthemorrhage increased during hemorrhage, and MAPs settled at about 50 mm Hg posthemorrhage (Table 2).
The results demonstrated that the greatest heart rate occurred posthemorrhage, which then stabilized toward the baseline with time (Table 3). Arterial pressure was noted to be the lowest posthemorrhage, increased, then stabilized. Average baseline total Hb was 15.1 g/dL, and average baseline Hct was 43.4% (N = 107; 13 dogs did not have baseline Hb and Hct). Average posthemorrhage total Hb was 12.1 g/dL, and average posthemorrhage Hct was 35.3% (N = 103; 17 dogs did not have posthemorrhage Hb and Hct). For total Hb, a difference of 3.0 (95% CI, 2.6 to 3.4; P < .001) was observed (Figure 1). For Hct, a difference of 8.3 (95% CI, 7.2 to 9.3; P < .001) was seen (Figure 2). Lactate significantly increased (2.1; P < .001), and base deficit significantly decreased (5.2; P < .001) (Table 3).
Baseline versus posthemorrhage values.
| Variables | Pre | Post | Difference (95% CI) | P value | n |
|---|---|---|---|---|---|
| Hb (g/dL) | 15.1 (1.6) | 12.1 (1.8) | −3.0 (−3.4 to 2.6) | < .001 | 103 |
| Hct (%) | 43.4 (5.0) | 35.3 (5.2) | −8.2 (−9.3 to 7.2) | < .001 | 103 |
| Lactate (mmol/L) | 1.2 (0.5) | 3.3 (1.3) | 2.1 (1.8 to 2.4) | < .001 | 69 |
| Base deficit (mmol/L) | −1.9 (3.1) | −7.1 (2.9) | −5.2 (−6.0 to 4.3) | < .001 | 81 |
Values reported are mean (SD).
Hb = Hemoglobin.
P values and 95% CIs were generated from the paired-samples t test.
To evaluate the changes in Hct and Hb pre- and posthemorrhage, a complete case analysis approach was utilized. Although there were a total of 120 verified animals/dogs/experiments, there were some experiments that had data for both Hb and Hct, whereas others had data for only 1 of these measures because in some cases, complete data could not be recorded through the completion of resuscitation, leading to a decrease in sample size from pre- to posthemorrhage (eg, N pre/post = 107/103 for Hb and 107/103 for Hct). As a result, all available values from these experiments were included in summarizing the pre- and postdata, but in the analysis comparing pre- and postvalues, or potential correlations between measures, only animals with complete data were utilized.
Lactate concentrations were measured in some of the studies. Because of this, only 8 experiments from 2 of the 4 studies6,8 reviewed had complete data for lactate and base deficit measurements, and so these were the only recorded results.
To evaluate the changes in blood pressure pre- and posthemorrhage, the following criteria were used to include and exclude experiments: out of 120 total dog experiments, 34 were able to be statistically evaluated because these were the only studies5–8 that had full documentation recordings for blood pressure and heart variables from prehemorrhage through posthemorrhage. The rationale behind this selection was that animals that were able to withstand the full experiment with resuscitation serve as better examples of human clinical comparisons. The animals that did not survive the protocol were excluded from the analysis. The study protocol utilized in this evaluation is graphically described in Table 1.
Discussion
Multiple scientific publications have reminded the reader that “we bleed whole blood” during acute blood loss and that Hb and Hct values likely should remain unchanged during acute hemorrhage. However, studies1–4 that have evaluated this relationship in the setting of acute trauma emergencies have demonstrated that there is a decrease in both Hb and Hct during these hemorrhagic events. Resuscitation with fluids (which causes hemodilution and may be a contributor to these observed decreases in Hb and Hct) administered to these victims may be difficult to measure accurately and precisely during trauma and emergent resuscitation, and hence this study with a methodical protocol in patients is almost impossible to perform. The role that fluids play in the decrease of Hb and Hct is challenging to investigate clinically.4 To account for this, we studied a canine hemorrhagic shock model in a controlled environment and collected data retrospectively from previously published studies5–8 that were not evaluating this research question specifically. We then used the data extracted from this study to validate the model for significant hypotension to evaluate whether it can accurately predict the degree of hemorrhage.
Various values, including MAP, heart rate, Hb, Hct, lactate concentration, and base deficit, were recorded prehemorrhage and posthemorrhage in 120 splenectomized mixed-breed dogs. The spleen is a contractile organ in dogs and can serve as an autotransfusion mechanism.5–8 One dog was noted to have a dramatic increase in Hb/Hct, which had been unexplained until it was noted that this dog had a supernumerary spleen, which likely autotransfused the animal prior to realization and excision. To reflect biological diversity, all attempts were made not to eliminate unusual data.
First, we observed the highest heart rate and lowest arterial pressure posthemorrhage, which strengthens the validity of the model by demonstrating significant hypotension. We also observed that Hb, Hct, and base deficit decrease posthemorrhage and that lactate concentration increases in this controlled setting, suggesting that they may be integrated in formulating resuscitation decisions of Hb- versus non–Hb-containing solutions.9
However, given the emergent nature of these events, nonoxygen transporting fluids (which may cause hemodilution and thus be a main contributor to these observed decreases in Hb and Hct) given to these patients may be difficult to measure accurately and precisely as the patients’ lives during trauma take precedence over recording specific values for a clinical study. It may be challenging to assess the role that non–Hb-containing fluids play in the decrease of Hb and Hct. To account for this, this study uses a dog model in a controlled environment. In addition, one needs to consider that the animals were infused with lactated Ringer solution at initially 10 mL/kg/h during open laparotomy until closure of the abdomen, then reduced to 5 mL/kg/h post induction of anesthesia and during instrumentation up to the moment of baseline measurements and then stopped. Hence, during hemorrhage, interstitial fluids from this infusion may have been recruited into the circulatory system, partially explaining the decrease in Hb and Hct; however, the data on lactate and base deficit would also be expected to decrease in the case of lactate and increase in the case of base deficit, if this were a factor, and they did not. The fact that the Hb/Hct decreased in every case but 1 and the lactate/base deficit increased suggests that there was not a massive fluid shift; otherwise, the lactate/base deficit would have decreased. Unfortunately, this study did not differentiate between hypovolemia, severe anemia, and/or vasoconstriction as the cause of the hypotension; therefore, we can only opine that Hb/Hct, lactate, and base deficit may predict severity of hemorrhage and possibly guide therapy.
Hemorrhagic shock is a life-threatening condition characterized by inadequate tissue perfusion due to acute blood loss. To understand its complex pathophysiology and develop effective treatments, researchers rely on experimental models.
The Wigger model, named after Carl J. Wiggers, is a widely used experimental model in hemorrhagic shock research involving controlled hemorrhage in laboratory animals to simulate the physiological responses observed in humans during hemorrhagic shock.
The Wigger model of hypovolemic shock has been a well-described model for more than 80 years.5,10
By adjusting the severity and duration of hemorrhage, researchers can mimic various clinical scenarios and assess the efficacy of interventions. The Wigger model has some important strengths that make it invaluable for experimental hemorrhagic shock research. It replicates key physiological responses seen in humans during hemorrhagic shock, including alterations in blood pressure, heart rate, tissue perfusion, and organ dysfunction.10 Further, researchers can precisely control the amount and rate of hemorrhage in the Wigger model, enabling standardized experiments and comparisons between interventions.11 Finally, the model allows for the study of hemorrhagic shock and potential treatments in a controlled laboratory setting without subjecting human subjects to the risks associated with acute blood loss.
However, there are some limitations of the Wigger model that need to be considered. Despite physiological similarities, there are inherent differences between animal models and humans in terms of anatomy, physiology, immune response, and pharmacokinetics, limiting direct translation to clinical practice.12
Further, the acute nature of hemorrhagic shock induced in animal models may not fully capture the complexity and long-term consequences observed in human patients, particularly in chronic or repeated blood loss scenarios. Also, variability in animal strains, age, sex, and housing conditions can influence experimental outcomes, making it challenging to standardize protocols across different research groups.13,14
Importantly, the use of animal models raises ethical concerns regarding animal welfare and unnecessary suffering, necessitating ethical oversight and adherence to guidelines.
To summarize, the Wigger model has been instrumental in advancing our understanding of hemorrhagic shock and evaluating potential therapeutic interventions. While it offers physiological relevance, experimental control, and ethical considerations, it also presents limitations, such as species differences, standardization challenges, and ethical concerns. By critically assessing the Wigger model and integrating findings from relevant literature, researchers can optimize its utility and address its limitations, ultimately improving clinical outcomes for patients with hemorrhagic shock.
Studies15,16 have indicated that dogs resuscitated with Hb-based oxygen carriers may not survive when their nadir Hb levels are similar to those observed in humans. This discrepancy is primarily due to species-specific differences in oxygen delivery and Hb function.
In humans, Hb levels as low as 7 g/dL are often considered acceptable in certain clinical situations. However, dogs have a higher baseline Hb concentration, typically ranging from 12 to 18 g/dL. Their physiological systems are adapted to these higher levels, and a significant drop can lead to inadequate tissue oxygenation. An additional confounder may be changes in total protein; however, these were not measured in the initial prospective studies.5–8,17
In summary, multiple values, including Hb and Hct, were recorded pre- and posthemorrhage in 120 mixed-breed dogs. The validation of this canine hemorrhagic shock model will enable further work comparing baseline and postresuscitation Hct, Hb, lactate concentration, and base deficit, which may prove to be critical in dictating which resuscitation strategies to implement in traumatic hemorrhage where only point-of-care monitoring may exist (ie, artificial oxygen carriers when blood is unavailable). We observed that both Hb and Hct decrease posthemorrhage in this controlled setting. Subsequent investigations should focus on evaluating the impact of different fluid resuscitation strategies on lactate and base deficit changes in traumatic hemorrhage, with the aim of refining clinical management protocols. The changes observed posthemorrhage were modest, though significant, and hence may serve as a signal of the severity of blood loss and therefore help guide therapeutic decisions.
Acknowledgments
The authors thank Rubie Choi for her assistance with text editing.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
ORCID
J. S. Jahr https://orcid.org/0000-0002-0131-9879
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