The microcirculation is where oxygen, carbon dioxide, nutrients, and metabolic waste exchange takes place. Studies1 have shown that the microcirculation can be compromised in shock and may become incoherent with macrocirculatory variables such as heart rate, cardiac output, and blood pressure. Currently, sublingual microcirculation assessed by bedside handheld videomicroscopy is the most common method to evaluate microcirculation and has been studied in healthy cats.2,3 However, image acquisition is highly prone to artifacts, and the validated method for evaluation is labor intensive. Moreover, sublingual videomicroscopy is a static measurement of microcirculation and may not fully reflect microvascular (dys)function. In contrast, tissue autoregulation responds to shear stress, local stimuli, metabolites, and myogenic changes to maintain tissue perfusion and is impaired in illness.4 A local thermal challenge assesses the cutaneous microcirculation reactivity and has been proposed as a method for evaluating microcirculatory (dys)function.5 This technique has shown promising results in human patients with shock, aiding in diagnosis, monitoring, and prognosis using cutaneous laser Doppler flowmetry.6,7 The aim of this study was to perform a proof of concept study to investigate the feasibility of using local cutaneous thermal challenge to assess microvascular reactivity in anesthetized cats and to observe the changes in moderate hemorrhage and equal volume isotonic crystalloid bolus in anesthetized cats. The hypothesis tested was that microvascular reactivity measurement is feasible in healthy, anesthetized cats and that moderate hemorrhage will decrease measured microvascular reactivity, while isotonic crystalloid bolus will restore microvascular reactivity measurement to baseline.
Methods
Animals
This study was part of a larger nonsurvival project involving 12 adult, healthy, purpose-bred cats. Cats were deemed healthy via normal findings on physical examination, CBC count, and serum biochemistry panel. The NIH guidelines and local laws and regulations were adhered to for the care of the cats. The Auburn University IACUC approved this study.
Anesthesia
Cats were sedated with alfaxalone (2 mg/kg, IM) and midazolam (0.2 mg/kg, IM). A 20-gauge 1.5-inch IV catheter was placed in the cephalic vein, and anesthesia was induced with alfaxalone IV to effect. After orotracheal intubation, the cats were kept in a sternal position, and general anesthesia was maintained with fentanyl infusion (3 to 10 μg/kg/h) and isoflurane in oxygen using an anesthesia workstation. The cats were mechanically ventilated throughout the experiment with peak inspiratory pressure of 10 cm H2O. End-tidal carbon dioxide partial pressure was targeted between 35 and 45 mm Hg by adjusting the respiratory rate.
Instrumentation
Once anesthetized, a 3-F femoral arterial catheter (PiCCO; Getinge) was placed via a standard cut-down technique, and a 20-gauge single-lumen central venous catheter was placed through the jugular vein. The level of the central venous catheter tip was adjusted according to the pressure waveform and verified postmortem. Both the arterial catheter and central venous catheter were connected to a multiparameter monitor through a brand new, single-use, fluid-filled transducer, positioned at the level of the manubrium, and zeroed to atmospheric pressure. The arterial catheter was continuously flushed with heparinized saline with a pressurized bag. A perivascular ultrasound transit time flow probe (8- to 10-mm PAU; Transonic) was placed around the main pulmonary artery through a lateral thoracotomy surgical approach after aseptic preparation of the surgical site. Ultrasound gel was applied between the flow probe and the pulmonary artery to ensure an acceptable signal according to the manufacturer’s recommendation. A chest tube was placed before the thorax was closed. Air and fluid were evacuated intermittently from the chest throughout the study. The perivascular ultrasound transit time flow probe was connected to a console (TS420; Transonic), and the console was connected to a data acquisition device (Powerlab 4/26; ADInstruments) to convert the analog signal to digital data which was then stored in a computer by commercially available software (LabChart; ADInstruments). A multiparameter monitor (Philips; MP70) was used to monitor heart rate, electrocardiography, respiratory rate, end-tidal carbon dioxide partial pressure, end-tidal isoflurane concentration, arterial blood pressure, and central venous pressure. Finally, an indwelling urinary catheter was placed and connected to a closed system for urine collection.
Treatments
After instrumentation, measurements were taken in 3 phases (Figure 1): (1) baseline, (2) hemorrhage, and (3) isotonic crystalloid bolus. Baseline measurements were recorded 20 minutes after instrumentation. Then, hemorrhage was induced by removing 20 mL/kg of blood through the central venous catheter by hand over 20 minutes. Twenty minutes later, posthemorrhage measurements were then recorded. Finally, an isotonic crystalloid (pHyLyte; Dechra) bolus was administered through the cephalic vein at 20 mL/kg over 20 minutes with a fluid pump. After another 20-minute period was allowed for hemodynamic stabilization, the final postfluid bolus measurement was recorded.
Experimental design and timeline. A total of 12 cats were used, and 6 cats were included in the analysis. The median and range of measurement time and additional amount of saline administered during baseline and after hemorrhage measurements are indicated. FB = 20 mL/kg isotonic crystalloid fluid bolus over 20 minutes. H = 20 mL/kg hemorrhage over 20 minutes. IVC = IV catheterization. S = Stabilization period.
Citation: American Journal of Veterinary Research 86, 1; 10.2460/ajvr.24.09.0262
Measurements
Measurements and sampling were performed in the same order: (1) multiparameter monitor variables and cardiac output, (2) arterial and central venous blood sampling for blood gas analysis, and (3) microvascular reactivity through a local cutaneous thermal challenge and laser Doppler flowmetry. Cardiac output was measured with additional 3 different methods for another study: transpulmonary thermodilution, transpulmonary ultrasonic dilution, and esophageal Doppler flow probe. Blood gas was performed immediately after sampling from the arterial catheter and central venous catheter. At least 1 mL of diluted blood was removed from the catheters before sampling. The diluted blood was reinfused through a central venous catheter afterward.
Cutaneous microcirculation was assessed with a laser Doppler flowmetry probe (MOORVMS-LDF; Moor Instruments). The probe has an emitting fiber that emits laser into the tissue and a receiving fiber that transmits the reflected and backscattered light to a photon detector while simultaneously measuring the skin temperature. When the laser encounters a moving object such as RBCs, a Doppler shift appears. The machine then analyzes the signal and generates measurements of flow in arbitrary units. The measurement volume of laser Doppler flowmetry is affected by the power of the laser, the distance between the emitting and receiving fiber, and the tissue characteristics. Typically, a 0.5- to 1-mm skin depth of blood flow is measured. An additional heating unit (MOORVMS-HEAT) was used to perform the local cutaneous thermal challenge and assess the microcirculation reactivity. Both probes were attached to a double-sided adhesive probe holder over the skin above the metatarsal pad of the hind limbs after shaving and gentle cleaning (Figure 2). Skin blood flow and temperature were recorded at baseline for each measurement with at least 3 minutes of stabilization without heating. The thermal challenge is performed by heating the skin to 37 °C at the rate of 0.1 °C per minute. A total of 5 minutes of stabilization was maintained once the temperature reached 37 °C, and readings were taken at the end of the stabilization period. The target temperature, 37 °C, is lower than the nociceptive thermal threshold in conscious cats; therefore, concerns for tissue damage are minimal.8 The microcirculation reactivity was calculated as the blood flow difference between 37 °C, and the baseline was divided by the temperature difference between 37 °C and the baseline.9
Pictures of laser Doppler flowmetry (A; lateral view) and heating unit placement (B; anterior-posterior view).
Citation: American Journal of Veterinary Research 86, 1; 10.2460/ajvr.24.09.0262
Variables such as cardiac index, stroke volume index, systemic vascular resistance index (SVRI), arterial and central venous oxygen contents, and oxygen delivery index were calculated using standard formula10 and indexed according to recent recommendations.11 Due to a lack of a mixed venous blood sample, oxygen consumption was calculated using a central venous blood sample. The carbon dioxide gap was the difference between arterial and central venous carbon dioxide partial pressure.
Statistical analysis
Power analysis and sample size calculation were not performed and the number of subjects was a convenient sample size. Age and weight are presented as median (IQR). Linear mixed effect model from lmer() function of lmerTest package in R was fitted to analyze all variables with subject as random effect and phases as fixed effect. The built-in anova() function in R was used to test type III ANOVA for the significance of phases. The estimated marginal mean and 95% CI from the linear mixed effect model were estimated using emmeans package in R. Additionally, the pairs() function from emmeans package in R was used for multiple comparisons. The Tukey method was applied for multiplicity adjustment. Significance was defined as P < .05. All analysis was performed in the RStudio IDE, version 2023.06.0 + 421 (RStudio Team; 2022), and R, version 4.4.0 (2024-04-24; R Core Team; 2022).12
Results
Due to surgical complications and equipment malfunction, microvascular reactivity data were obtained in only 6 cats. Of the 6 cats that were excluded, 1 was used for the pilot study, 2 had surgical complications that prohibited further measurements, 1 had a kinked arterial catheter, and 2 had laser Doppler flowmetry malfunction resulting in no usable data. The age was 6.7 (1.7 to 8.3) years old, and the weight was 3.47 (3.25 to 3.62) kg.
The duration and amount of saline used for additional cardiac output measurements are provided (Figure 1). The median (range) duration after baseline and hemorrhage was 40 (27 to 69) minutes and 44 (24 to 75) minutes, respectively. The median (range) of saline used for additional cardiac output measurements from transthoracic methods at baseline and hemorrhage was 4.3 (3.8 to 6.4) mL/kg and 4.8 (3.9 to 6.9) mL/kg.
Microvascular reactivity in each phase is provided (Figure 3). Microvascular reactivity decreased significantly after hemorrhage (P = .0067) but did not significantly increase after the fluid bolus (P = .91) and remained significantly lower than baseline after the fluid bolus (P = .013).
Box and violin plot of microvascular reactivity. The solid lines indicate the median, and the dotted lines indicate the IQR. *P < .05 for the pair comparison.
Citation: American Journal of Veterinary Research 86, 1; 10.2460/ajvr.24.09.0262
A summary of the hemodynamic variables is provided (Table 1). The hemodynamic variables showed significant changes compared to the baseline after hemorrhage, including increased heart rate (P = .00037), decreased cardiac index (P = .0005), and stroke volume index (P < .0001). After the fluid bolus, heart rate did not change significantly compared to after hemorrhage (P = .51) and remained significantly increased compared to baseline (P = .0018), while cardiac index increased significantly compared to after hemorrhage (P = .0007) and was not significantly different from baseline (P = .94). However, stroke volume index increased significantly compared to after hemorrhage (P = .0006) but remained significantly lowered than baseline after the fluid bolus (P = .033).
Hemodynamic variables and blood gas analysis of the 6 anesthetized cats after hemorrhage (20 mL/kg over 20 minutes) and isotonic crystalloid fluid bolus (20 mL/kg over 20 minutes).
| Baseline | Hemorrhage | Fluid bolus | |
|---|---|---|---|
| HR (beats/min) | 160 (146–174)a | 193 (179–207)b | 187 (172–200)b |
| SAP (mm Hg) | 124 (94–153) | 107 (78–137) | 96 (66–126) |
| MAP (mm Hg) | 86 (69–103)a | 63 (46–81)a,b | 58 (40–75)b |
| DAP (mm Hg) | 64 (53–76)a | 45 (33–57)b | 39 (28–51)b |
| CVP (mm Hg) | 3.3 (1.0–6.0)a | 2.3 (0.1–4.6)b | 3.0 (0.7–5.3)a,b |
| CI (mL/kg0.67) | 0.14 (0.11–0.18)a | 0.09 (0.06–0.12)b | 0.14 (0.11–0.17)a |
| SVI (mL/kg) | 0.60 (0.47–0.72)a | 0.32 (0.19–0.44)b | 0.50 (0.37–0.63)c |
| SVRI (dyne/s/cm5/kg0.67) | 9,209 (6,817–11,601)a,b | 10,730 (8,338–13,122)a | 6,747 (4,355–9,139)b |
| RR (breaths/min) | 14 (4–25) | 17 (6–28) | 23 (13–33) |
| ETiso (%) | 1.5 (1.3–1.6)a | 1.6 (1.4–1.7)a,b | 1.7 (1.6–1.9)b |
| Temp (°C) | 36.4 (35.7–37.2)a | 37.5 (36.7–38.2)b | 37.6 (36.8–38.4)b |
| Pao2 (mm Hg) | 358 (306–410) | 375 (323–427) | 414 (362–466) |
| VpH | 7.27 (7.22–7.32)a | 7.23 (7.18–7.27)b | 7.25 (7.20–7.30)a,b |
| VPo2 (mm Hg) | 82.3 (53.5–111.1)a | 57.5 (28.6–86.3)b | 72.1 (43.2–100.9)a,b |
| VPco2 (mm Hg) | 40 (32–48) | 44 (36–52) | 42 (34–50) |
| VHGB (g/dL) | 8.6 (7.1–10.0)a,b | 10.0 (8.6–11.4)a | 8.3 (6.9–9.8)b |
| VHco3 (mEq/L) | 17.8 (14.3–21.1) | 18.2 (14.9–21.6) | 18.7 (15.3–22.1) |
| Scvo2 (%) | 90.6 (80.4–100.8)a | 75.3 (65.2–85.5)b | 81.9 (71.8–92.1)a,b |
| Cao2 (mL/dL) | 14.0 (11.6–16.4)a | 14.6 (12.2–17.0)a | 12.1 (9.7–14.5)b |
| Cvo2 (mL/dL) | 11.1 (8.4–13.8) | 10.8 (8.0–13.5) | 9.8 (7.1–12.6) |
| Do2I (mL/min/kg0.67) | 19.6 (14.72–24.5)a | 13.3 (8.43–18.3)b | 16.9 (12.01–21.8)a,b |
| Vo2I (mL/min/kg0.67) | 3.42 (0.593–6.25) | 3.08 (0.255–5.91) | 2.75 (0–5.58) |
| OER | 0.19 (0.0–0.38) | 0.26 (0.07–0.45) | 0.19 (0.0–0.38) |
| CO2 gap (mm Hg) | 4.3 (1.2–7.5)a | 9.2 (6.5–12.0)a,b | 10.1 (7.3–12.9)b |
Cao2 = Arterial oxygen content. CI = Cardiac index. CO2 gap = Arterial to central venous carbon dioxide partial pressure difference. Cvo2 = Central venous oxygen content. CVP = central venous pressure. DAP = Diastolic arterial pressure. Do2I = Oxygen delivery index. ETiso = End-tidal isoflurane concentration. HR = Heart rate. MAP = Mean arterial pressure. Pao2 = Arterial oxygen partial pressure. OER = Oxygen extraction ratio. RR = Respiratory rate. SAP = Systolic arterial pressure. Scvo2 = Central venous oxygen partial pressure. SVI = Stroke volume index. SVRI = Systemic vascular resistance index. Temp = Temperature. VHco3 = Venous bicarbonate concentration. VHGB = Venous hemoglobin concentration. Vo2I = Oxygen consumption index. VPco2 = Venous carbon dioxide partial pressure. VpH = Venous pH. VPo2 = Venous oxygen partial pressure.
Statistical significantly differences between phases.
Systolic arterial blood pressure was not significantly different between phases (P > .22). Mean arterial pressure was not significantly different after hemorrhage (P = .073) or after the fluid bolus (P = .83) compared to the previous phase. However, the mean arterial pressure was significantly lower than the baseline after the fluid bolus (P = .028). Diastolic arterial pressure was significantly lower after hemorrhage (P = .03) and did not change significantly after the fluid bolus compared to after hemorrhage (P = .63) and remained significantly lower than the baseline after the fluid bolus (P = .0068). The SVRI did not change significantly after hemorrhage (P = .34) but was significantly lower after the fluid bolus compared to after hemorrhage (P = .0083). However, SVRI was not significantly lower than baseline after the fluid bolus (P = .09).
Hemorrhage significantly decreased oxygen delivery compared to the baseline (P = .018) and did not significantly improve after fluid bolus compared to after hemorrhage (P = .18), although oxygen delivery after the fluid bolus was not significantly different from baseline (P = .35). Additionally, hemoglobin concentration was not significantly different after hemorrhage (0.074) and was not significantly different from baseline after fluid bolus (P = .91) but was significantly lower after the fluid bolus compared to after hemorrhage (P = .038). In contrast, arterial oxygen content was not significantly different after hemorrhage (P = .65) but decreased significantly after the fluid bolus compared to after hemorrhage (P = .009) and was significantly lower than baseline (0.039). Central venous oxygen saturation significantly decreased after hemorrhage (P = .003) and did not significantly increase after the fluid bolus compared to after hemorrhage (P = .17). However, there were no significant differences in central venous oxygen saturation after the fluid bolus compared to baseline (P = .69), and the estimated marginal mean of central venous oxygen saturation was higher than 75% for all phases. The carbon dioxide gap did not significantly change after hemorrhage compared to baseline (P = .073) or after the fluid bolus compared to after hemorrhage (P = .88) but was significantly higher after the fluid bolus than baseline (P = .035).
Discussion
This study demonstrated that microvascular reactivity decreased after hemorrhage and did not return to baseline after the isotonic crystalloid fluid bolus given in this study in healthy anesthetized cats. Overall, hemorrhage decreased cardiac index, oxygen delivery, and central venous oxygen saturation and increased heart rate despite varied arterial blood pressure responses. Isotonic crystalloid bolus improved cardiac index and stroke volume index but did not improve heart rate, oxygen delivery, and central venous oxygen saturation. Additionally, the SVRI significantly decreased after the fluid bolus, and mean and diastolic arterial blood pressure was significantly lower than baseline after the fluid bolus.
Cutaneous responses to local warming have a complex mechanism involving sensory nerves, the endothelium, and the adrenergic system in humans.13 At the beginning of rapid submaximal warming (below 42 °C), vasodilation is primarily caused by axon reflex mediated by sensory nerves. Subsequently, nitric oxide release becomes the dominant mechanism.13 Throughout the vasodilation response, the adrenergic system is significantly involved and counterintuitively facilitates, but not inhibits, the vasodilation response.13 Due to the gradual warming rate, target temperature, and timing of measurement, the blood flow changes measured in this study are likely a mix of all of the above mechanisms. However, there is a lack of cat-specific data therefore the exact mechanisms remained unclear.
The microvascular reactivity assessed by a local cutaneous thermal challenge was first used in acute medicine in human patients undergoing cardiac surgery on cardiopulmonary bypass.14 Numerous studies6,7,9,15–17 have subsequently shown that microvascular reactivity assessed by a local thermal challenge consistently provides diagnosis, prognosis, and monitoring information in humans despite a wide variety of protocols used. Specifically, the microvascular reactivity from a local cutaneous thermal challenge was assessed in clinical patients with circulatory shock.6,7 In both studies,6,7 patients with circulatory shock and nonsurvivors had lower microvascular reactivity compared to healthy controls and survivors. The lower microvascular reactivity in patients with shock is consistent with the results in this study, demonstrating a decrease in microvascular reactivity following hemorrhage. However, the microvascular reactivity did not return to baseline after fluid bolus despite improvements in cardiac index and stroke volume index in this study. This may be due to persistent microvascular dysfunction. However, the absence of a control group makes it difficult to rule out the effects of time. Further research is therefore required to replicate these findings. In this study, an equal volume crystalloid bolus to hemorrhage was administered based on the principles of limited volume resuscitation and the common clinical practice of dosing fluid boluses in aliquots. Nevertheless, it is possible that higher volume resuscitation could restore microvascular reactivity to baseline levels. Further research is warranted to explore this possibility.
Hemodilution, heterogeneity, microvascular RBC stasis, and interstitial edema have been proposed as the mechanisms of microcirculatory dysfunction.18 After hemorrhage, microvascular RBC stasis and heterogeneity may have contributed to the observed microvascular dysfunction. Although no statistically significant difference in hemoglobin concentration was found between baseline and postbolus measurements, crystalloid infusion may have altered blood viscosity, resulting in persistent microvascular heterogeneity. Additionally, the bolus could have induced interstitial edema, further contributing to the dysfunction. Future studies should consider incorporating direct assessments of sublingual microcirculation using handheld video microscopy to better explore these underlying mechanisms. It is important to note that interindividual variability at baseline may limit clinical use. Additionally, microvascular reactivity has not been fully validated. The optimal measurement protocol, including the location, definition of baseline, target temperature, rate of warming, and duration of warming, remains to be determined. However, this study showed using local cutaneous thermal challenge and laser Doppler flowmetry to assess microvascular reactivity is feasible. The validity, reliability, and reproducibility of the microvascular reactivity remains to be determined in animals. Therefore, more studies on target species of veterinary medicine are warranted.
Interestingly, the heart rate increased after hemorrhage in this study, despite the anecdotal notion that cats tend to show bradycardia in shock. A proposed mechanism of bradycardia has been a lack of or a very short-lived compensatory phase.19 However, that study19 used an endotoxic shock model, and the responses to endotoxins in cats have been inconsistent across studies, likely due to the different endotoxins used.20–22 Additionally, conflicting results exist in the literature regarding heart rate changes in feline hemorrhage models.23,24 This discrepancy may be explained by the severity and the speed of hemorrhage as more severe and rapid hemorrhage tends to cause bradycardia.24 In the case of rapid and/or severe hemorrhage in cats, the underlying mechanism of bradycardia was initially attributed to a vaso-vagal response.24 Activation of left ventricular receptors in hypovolemia was identified as a possible cause of the vaso-vagal response.25 This vaso-vagal response was later known as cardioinhibitory type Bezold-Jarisch reflex, induced by mechanical stimulation, in contrast to the classic Bezold-Jarisch reflex induced by chemical stimulation of the left ventricle.26 Additionally, atrial type B receptors have been proposed to change heart rate in response to blood volume, also known as the Bainbridge and reverse Bainbridge reflex.27 Although cats’ atrial type B receptors do respond to volume changes,28 the Bainbridge and reverse Bainbridge reflex are not unique to cats.27 Moreover, bradycardia resulting from severe and/or rapid hemorrhage is not exclusive to cats; it has also been observed in humans, dogs, and rats.29 Based on the findings of this study and supported by existing literature,23 it is likely that cats respond to hemorrhage similarly to many other mammals, at least under isoflurane anesthesia.
Nevertheless, it is important to distinguish the physiological responses to hemorrhage in cats, the responses to treatment in hypovolemic cats, and the responses in cats with shock in general. Clinically, the feline patient in shock tends to present with the triad of bradycardia, hypothermia, and hypotension. The complex interplay has been discussed in a textbook19 and may explain why volume expansion often improves blood pressure but fails to reverse shock in cats.30 Clinicians should still exercise caution when using fluid therapy in feline shock resuscitation.
There are several strengths and limitations in this study. Invasive hemodynamic and blood gas measurements allow detailed information to be obtained in each phase. However, the small sample size, cats being anesthetized, and the laboratory setting limit the external validity despite statistically significant differences in microvascular reactivity between phases. Moreover, applying a regression model in a small sample size may increase the chances of both false positive and false negative results.31 Small sample sizes may also limit the power and overestimate effect size. Additionally, the hemorrhagic shock model was induced by fixed-volume atraumatic blood loss. This type of model is less reproducible and reliable but allows normal compensatory responses compared to the fixed pressure model.31 Moreover, the timeline and the amount of additional saline administered were not standardized. This may introduce additional bias to the results. However, one may also argue that this inconsistency more closely mimics the clinical scenario. This study only used one probe to measure microvascular reactivity. It has been shown that multiple probes improve the reproducibility of laser Doppler flowmetry and should be considered in the future.32 Finally, due to the body size limitation and technical challenges, this study measured central venous blood gas but not mixed venous blood gas. Significant differences between central versus mixed venous sulfur dioxide in cats after hemorrhage have been shown in a previous study.33
In conclusion, microvascular reactivity assessed by a local cutaneous thermal challenge and laser Doppler flowmetry was feasible in healthy anesthetized cats, but proper validation is warranted before clinical application.
Acknowledgments
The authors thank Scott-Ritchey Research Center, Jessica Cannon, and Taylor Moss for collaboration and technical support.
Disclosures
The authors have nothing to disclose.
ChatGPT was used for the revision of this manuscript.
Funding
This study was supported by start-up funds from the Department of Clinical Sciences of Auburn University.
ORCID
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