Goal-directed colloid versus crystalloid therapy and microcirculatory blood flow following ischemia/reperfusion.

OBJECTIVE: Ischemia/reperfusion can impair microcirculatory blood flow. It remains unknown whether colloids are superior to crystalloids for restoration of microcirculatory blood flow during ischemia/reperfusion injury. We tested the hypothesis that goal-directed colloid - compared to crystalloid - therapy improves small intestinal, renal, and hepatic microcirculatory blood flow in pigs with ischemia/reperfusion injury. METHODS: This was a randomized trial in 32 pigs. We induced ischemia/reperfusion by supra-celiac aortic-cross-clamping. Pigs were randomized to receive either goal-directed isooncotic hydroxyethyl-starch colloid or balanced isotonic crystalloid therapy. Microcirculatory blood flow was measured using Laser-Speckle-Contrast-Imaging. The primary outcome was small intestinal, renal, and hepatic microcirculatory blood flow 4.5 h after ischemia/reperfusion. Secondary outcomes included small intestinal, renal, and hepatic histopathological damage, macrohemodynamic and metabolic variables, as well as specific biomarkers of tissue injury, renal, and hepatic function and injury, and endothelial barrier function. RESULTS: Small intestinal microcirculatory blood flow was higher in pigs assigned to isooncotic hydroxyethyl-starch colloid therapy than in pigs assigned to balanced isotonic crystalloid therapy (768.7 (677.2-860.1) vs. 595.6 (496.3-694.8) arbitrary units, p = .007). There were no important differences in renal (509.7 (427.2-592.1) vs. 442.1 (361.2-523.0) arbitrary units, p = .286) and hepatic (604.7 (507.7-701.8) vs. 548.7 (444.0-653.3) arbitrary units, p = .376) microcirculatory blood flow between groups. Pigs assigned to colloid - compared to crystalloid - therapy also had less small intestinal, but not renal and hepatic, histopathological damage. CONCLUSIONS: Goal-directed isooncotic hydroxyethyl-starch colloid - compared to balanced isotonic crystalloid - therapy improved small intestinal, but not renal and hepatic, microcirculatory blood flow in pigs with ischemia/reperfusion injury. Whether colloid therapy improves small intestinal microcirculatory blood flow in patients with ischemia/reperfusion needs to be investigated in clinical trials.

The impact of nitroglycerine and volume on gastric tube microperfusion assessed by indocyanine green fluorescence imaging.

The influence of hypervolemia and intraoperative administration of nitroglycerine on gastric tube microperfusion remains unclear The present study aimed to investigate the impact of different hemodynamic settings on gastric tube microperfusion quantified by fluorescence imaging with Indocyanine green (ICG-FI) as a promising tool for perfusion evaluation. Three groups with seven pigs each were formed using noradrenaline, nitroglycerin, and hypervolemia for hemodynamic management, respectively. ICG-FI, hemodynamic parameters, and transit-time flow measurement (TTFM) in the right gastroepiploic artery were continuously assessed. Fluorescent microspheres (FM) were administered, and the partial pressure of tissue oxygen was quantified. The administration of nitroglycerine and hypervolemia were both associated with significantly impaired microperfusion compared to the noradrenaline group quantified by ICG-FI. Even the most minor differences in microperfusion could be sufficiently predicted which, however, could not be represented by the mean arterial pressure measurement. Histopathological findings supported these results with a higher degree of epithelial damage in areas with impaired perfusion. The values measured by ICG-FI significantly correlated with the FM measurement. Using tissue oxygenation and TTFM for perfusion measurement, changes in microperfusion could not be comprehended. Our results support current clinical practice with restrictive volume and catecholamine administration in major surgery. Hypervolemia and continuous administration of nitroglycerine should be avoided.

Quantification of gastric tube perfusion following esophagectomy using fluorescence imaging with indocyanine green.

INTRODUCTION: Anastomotic leakage (AL) remains a prevalent and life-threatening complication after esophagectomy. Gastric tube perfusion assessment using indocyanine green fluorescence imaging (ICG-FI) has been published in several studies and appears to be a promising tool to reduce AL rates by changing the surgical approach, namely by an intraoperative evaluation of the anastomosis localization. METHODS: In this study, gastric tube perfusion was quantified by using ICG-FI in 20 high-risk patients undergoing esophagectomy. From a time-dependent fluorescence intensity curve, the following three parameters were evaluated: slope of fluorescence intensity (SFI), background subtracted peak fluorescence intensity (BSFI), and time to slope (TTS). RESULTS: The values between pyloric region and tip showed a similar downward trend and SFI and BSFI significantly correlated with the distance to the pyloric region. SFI and BSFI were significantly decreased at the tip of the gastric tube. The placement of anastomosis in an area with homogenous fluorescence pattern was correlated with no AL in 92.9% of cases. An inhomogeneous fluorescence pattern at anastomotic site was a risk factor for the occurrence of an AL (p < 0.05). Reduction of perfusion up to 32% using SFI and up to 23% using BSFI was not associated with AL. CONCLUSION: ICG-FI can be used to quantify the gastric tube perfusion by calculating SFI, BSFI, and TTS. The anastomosis should be created in areas with homogeneous fluorescence pattern. A reduction in blood flow of up to 32% can be accepted without causing an increased rate of insufficiency.

Effects of fluids vs. vasopressors on spinal cord microperfusion in hemorrhagic shock induced ischemia/reperfusion.

OBJECTIVE: Spinal cord injury induced by ischemia/reperfusion is a devastating complication of aortic repair. Despite developments for prevention and treatment of spinal cord injury, incidence is still considerably high majorly impacting patient outcome. Microcirculation is paramount for tissue perfusion and oxygen supply and often dissociated from macrohemodynamic parameters used to guide resuscitation. Effects of fluids vs. vasopressors in the setting of hemodynamic resuscitation on spinal cord microperfusion are unknown. Aim of this study was to compare the effects of vasopressor and fluid resuscitation on spinal cord microperfusion in a translational acute pig model of hemorrhagic shock induced ischemia/reperfusion injury. METHODS: We designed this study as prospective randomized explorative large animal study. We induced hemorrhagic shock in 20 pigs as a model of global ischemia/reperfusion injury. We randomized animals to receive either fluid or vasopressor resuscitation. We measured spinal cord microperfusion using fluorescent microspheres as well as laser-Doppler probes. We monitored and analyzed macrohemodynamic parameters and cerebrospinal fluid pressure. RESULTS: Spinal cord microperfusion decreased following hemorrhagic shock induced ischemia/reperfusion injury. Both fluids and vasopressors sufficiently restored spinal cord microperfusion. There were no important changes between groups (percentage changes compared to baseline: fluids 14.0 (0.31-27.6) vs. vasopressors 24.3 (8.12-40.4), p = .340). However, cerebrospinal fluid pressure was higher in animals receiving fluid resuscitation (percentage changes compared to baseline: fluids 27.7 (12.6-42.8) vs. vasopressors -5.56 ((-19.8)-8.72), p = .003). Microcirculatory resuscitation was in line with improvements of macrohemodynamic parameters. CONCLUSIONS: Both, fluids and vasopressors, equally restored spinal cord microperfusion in a porcine acute model of hemorrhagic shock induced ischemia/reperfusion injury. However, significant differences in cerebrospinal fluid pressure following resuscitation were present. Future studies should evaluate these effects in perfusion disruption induced ischemia/reperfusion conditions of microcirculatory deterioration.

Comparison of Prosthetic and Vein Bypass with Nitinol Stents in Long Femoropopliteal Lesions.

BACKGROUND: Guidelines for the treatment of long femoropopliteal lesions are not based on a high level of evidence and recent randomized controlled trials (RCTs) challenge vein bypass (VBP) as the recommended therapy. This study compared prosthetic (PTFE) bypass, VBP and angioplasty with nitinol stents in long femoropopliteal lesions. METHODS: Pooled data from a RCT and a retrospective database with the same inclusion criteria were analyzed with primary and secondary patency as well as freedom from target lesion revascularization (TLR) as primary endpoints. RESULTS: Between 2016 and 2018 a total of 172 lesions were treated in three groups (PTFE: n = 62, VBP: n = 55, stent: n = 55). Clinical and lesion characteristics were similar with mean lesion lengths between 260 and 279mm. Technical success rate in the stent group was 87%. There were no significant differences between the groups in patency rates, freedom from TLR, limb salvage and survival during 2-year follow-up. The primary patency rates for the PTFE, VBP and stent groups were 50%, 56% and 60% at 2 years. The PTFE group had significantly less complications compared to the other groups and a shorter hospital-stay compared to the VBP group. Clinical improvement was significantly better in the PTFE and VBP group compared to the stent group. CONCLUSIONS: The 2-year results indicate that the role of VBP as the recommended therapy for long femoropopliteal lesions may not be unchallenged due to the similar results in all three groups. Further RCTs are needed to determine the best revascularization modality for long femoropopliteal lesions.

Prevalence of VOYAGER PAD trial exclusion criteria in unselected patients undergoing lower limb revascularization.

BACKGROUND: The VOYAGER PAD trial investigated data on dual pathway inhibition after lower limb revascularization for peripheral arterial disease (PAD). Multiple exclusion criteria were applied. However, neither data on the prevalence of exclusion criteria nor on the total number of patients screened for inclusion was discussed. METHODS: We performed a single-center prospective observational study in unselected PAD patients undergoing lower limb revascularization. Demographic and disease-specific data was collected. RESULTS: One hundred fifty patients were included with only 29 patients (19.3%) as potential candidates for the VOYAGER PAD study medication. Poorly controlled diabetes or severe uncontrolled hypertension (33.3%), major tissue loss (18.7%), acute limb ischaemia within prior 2 weeks (17.3%) and a history of intracranial hemorrhage, stroke or TIA (16%) were amongst the exclusion criteria most frequently met. Compared to VOYAGER PAD study patients, significant differences regarding sex (36.7% female vs. 25.8%), renal insufficiency (29.0% vs. 20.1%), previous myocardial infarction (16.7% vs. 11.1%) and known carotid artery disease (18.7% vs. 8.6%) revealed. Patients presented significantly more frequently with critical limb ischemia (56.7% vs. 30.4%) and a history of previous peripheral revascularization (72.0% vs. 35.9%). Fewer endovascular interventions (52% vs. 65.5%) and more surgeries (58% vs. 34.5%) were performed. CONCLUSIONS: In unselected patients undergoing revascularization for peripheral arterial disease, the majority presents with characteristics that, at present, preclude prescription of rivaroxaban in addition to aspirin. This patient cohort represents a population with higher rates of comorbidities and more complex vascular interventions, but might also benefit from dual pathway inhibition strategy.

Intraoperative quality assessment of tissue perfusion with indocyanine green (ICG) in a porcine model of mesenteric ischemia.

BACKGROUND: Mesenteric ischemia is a severe and potentially lethal event. Assessment of intestine perfusion is eminently depending on the skills, and the experience of the surgeon. Thus, the therapy is biased by the right evaluation. Aim of this study is to determine the applicability, and the usefulness of fluorescent-imaging (FI) with indocyanine green (ICG) in a porcine model of mesenteric ischemia. Second end-point is the verification of a visual and quantitative assessment tool of the intestinal perfusion. METHODS: In 18 pigs (54,2 ±2,9kg) an occlusion of a side-branch of the mesenteric artery was performed for 3 (group I, n = 7), 6 (group II, n = 7), and 10 hours (group III, n = 4). After reperfusion a 60 minutes observation period was carried out. 3 regions of interest were defined: ischemic bowel (D1), transitional zone (D2), and non-ischemic bowel (D3). ICG-FI was performed during baseline (T0), occlusion (T1), reperfusion (T2) and after an observation period of 60 minutes (T4). RESULTS: All experiments could be finished successfully. ICG-FI was assessed using assessment of background-subtracted peak fluorescence intensity (BSFI), slope of fluorescence intensity (SFI), and a baseline adjusted ratio of both parameters. ICG-FI confirmed loss of perfusion in D1, decreased perfusion in D2, and increased perfusion in D3. After reperfusion ICG-FI increased in group 2 due to a severe tissue damage resulting in a capillary leakage. In group I ICG-FI was equal to baseline values indicating the totally reversible loss of perfusion. CONCLUSION: Using ICG-FI to estimate intestine perfusion after different durations of ischemia is viable using a porcine model of mesenteric ischemia. Even small differences in perfusion can be reliably determined by ICG-FI. Thus, ICG-FI is an encouraging method to evaluate intestine perfusion intraoperatively.

The use of pulse pressure variation for predicting impairment of microcirculatory blood flow.

Dynamic parameters of preload have been widely recommended to guide fluid therapy based on the principle of fluid responsiveness and with regard to cardiac output. An equally important aspect is however to also avoid volume-overload. This accounts particularly when capillary leakage is present and volume-overload will promote impairment of microcirculatory blood flow. The aim of this study was to evaluate, whether an impairment of intestinal microcirculation caused by volume-load potentially can be predicted using pulse pressure variation in an experimental model of ischemia/reperfusion injury. The study was designed as a prospective explorative large animal pilot study. The study was performed in 8 anesthetized domestic pigs (German landrace). Ischemia/reperfusion was induced during aortic surgery. 6 h after ischemia/reperfusion-injury measurements were performed during 4 consecutive volume-loading-steps, each consisting of 6 ml kg-1 bodyweight-1. Mean microcirculatory blood flow (mean Flux) of the ileum was measured using direct laser-speckle-contrast-imaging. Receiver operating characteristic analysis was performed to determine the ability of pulse pressure variation to predict a decrease in microcirculation. A reduction of ≥ 10% mean Flux was considered a relevant decrease. After ischemia-reperfusion, volume-loading-steps led to a significant increase of cardiac output as well as mean arterial pressure, while pulse pressure variation and mean Flux were significantly reduced (Pairwise comparison ischemia/reperfusion-injury vs. volume loading step no. 4): cardiac output (l min-1) 1.68 (1.02-2.35) versus 2.84 (2.15-3.53), p = 0.002, mean arterial pressure (mmHg) 29.89 (21.65-38.12) versus 52.34 (43.55-61.14), p < 0.001, pulse pressure variation (%) 24.84 (17.45-32.22) versus 9.59 (1.68-17.49), p = 0.004, mean Flux (p.u.) 414.95 (295.18-534.72) versus 327.21 (206.95-447.48), p = 0.006. Receiver operating characteristic analysis revealed an area under the curve of 0.88 (CI 95% 0.73-1.00; p value < 0.001) for pulse pressure variation for predicting a decrease of microcirculatory blood flow. The results of our study show that pulse pressure variation does have the potential to predict decreases of intestinal microcirculatory blood flow due to volume-load after ischemia/reperfusion-injury. This should encourage further translational research and might help to prevent microcirculatory impairment due to excessive fluid resuscitation and to guide fluid therapy in the future.

Real-Time Assessment of Spinal Cord Microperfusion in a Porcine Model of Ischemia/Reperfusion.

Spinal cord injury is a devastating complication of aortic repair. Despite developments for the prevention and treatment of spinal cord injury, its incidence is still considerably high and therefore, influences patient outcome. Microcirculation plays a key role in tissue perfusion and oxygen supply and is often dissociated from macrohemodynamics. Thus, direct evaluation of spinal cord microcirculation is essential for the development of microcirculation-targeted therapies and the evaluation of existing approaches in regard to spinal cord microcirculation. However, most of the methods do not provide real-time assessment of spinal cord microcirculation. The aim of this study is to describe a standardized protocol for real-time spinal cord microcirculatory evaluation using laser-Doppler needle probes directly inserted in the spinal cord. We used a porcine model of ischemia/reperfusion to induce deterioration of the spinal cord microcirculation. In addition, a fluorescent microsphere injection technique was used. Initially, animals were anesthetized and mechanically ventilated. Thereafter, laser-Doppler needle probe insertion was performed, followed by the placement of cerebrospinal fluid drainage. A median sternotomy was performed for exposure of the descending aorta to perform aortic cross-clamping. Ischemia/reperfusion was induced by supra-celiac aortic cross-clamping for a total of 48 min, followed by reperfusion and hemodynamic stabilization. Laser-Doppler Flux was performed in parallel with macrohemodynamic evaluation. In addition, automated cerebrospinal fluid drainage was used to maintain a stable cerebrospinal pressure. After completion of the protocol, animals were sacrificed, and the spinal cord was harvested for histopathological and microsphere analysis. The protocol reveals the feasibility of spinal cord microperfusion measurements using laser-Doppler probes and shows a marked decrease during ischemia as well as recovery after reperfusion. Results showed comparable behavior to fluorescent microsphere evaluation. In conclusion, this new protocol might provide a useful large animal model for future studies using real-time spinal cord microperfusion assessment in ischemia/reperfusion conditions.

Validation of quantitative assessment of indocyanine green fluorescent imaging in a one-vessel model.

OBJECTIVES: Evaluation of intestinal perfusion remains subjective and depends on the surgeon´s individual experience. Intraoperative quality assessment of tissue perfusion with indocyanine green (ICG) fluorescence using a near-infrared camera system has been described in different ways and for different indications. The aim of the present study was to evaluate fluorescent imaging (FI) in the quantitative assessment of intestinal perfusion in a gastric tube model in pigs and to compare the results to results obtained with florescent microspheres (FM), the gold standard for tissue perfusion. METHODS: Seven pigs (56.0±3.0 kg), both males and females, underwent gastric tube formation after transection and ligation of the gastric arteries, except the right gastroepiploic artery, to avoid collateral blood flow. After baseline assessment (T0), hypotension (T1) was induced by propofol (Karampinis et al 2017) (< 60 mmHg). Then, propofol was paused to obtain normotension (T2, Mean arterial pressure (MAP) 60-90 mmHg). Finally, hypertension (T3, MAP>90 mmHg) was induced by norepinephrine. Measurements were performed in three regions of interest (ROIs) under standardized conditions: the fundus (D1), corpus (D2), and prepyloric area (D3). Hemodynamic parameters and transit-time flow measurement (TTFM) in the right gastroepiploic artery were continuously assessed. FI, FM and the partial pressure of tissue oxygen (TpO2) were quantified in each ROI. RESULTS: The study protocol could successfully be performed during stable hemodynamics. Flow in the gastroepiploic artery measured by transit time flow measurement (TTFM) was related to hemodynamic changes between the measurements, indicating improved blood flow with increasing MAP. The distal part of the gastric tube (D1) showed significantly (p<0.05) impaired perfusion compared to the proximal parts D3 and D2 using FM. ICG-FI also showed the highest values in D3 and the lowest values in D1 at all hemodynamic levels (T1-T3; p<0,05). CONCLUSION: Visual and quantitative assessment of gastric tube perfusion is feasible in an experimental setting using ICG-FI. This might be a promising tool for intraoperative assessment during visceral surgery in the future.

Volume Based Resuscitation and Intestinal Microcirculation after Ischaemia/Reperfusion Injury: Results of an Exploratory Aortic Clamping Study in Pigs.

OBJECTIVES: In the presence of ischaemia/reperfusion (I/R) induced endothelial injury, volume administration may not correlate with increased microcirculation. The aim of this study was to evaluate intestinal microcirculation after standardised sequential volume loading in an animal model of I/R injury following supracoeliac aortic clamping. METHODS: This was a prospective exploratory pilot animal study. Intestinal I/R injury was induced in eight pigs during experimental thoraco-abdominal aortic repair. After 6 h of I/R, microcirculatory blood flow (mFlux, measured in the ileum using direct laser speckle contrast imaging) and macrohaemodynamic parameters (using trans-cardiopulmonary thermodilution) were measured and measurements were repeated after each of four sequential volume loading steps (VLS1 - 4). Each load was administered over 5 min followed by another 5 min for equilibration. RESULTS: All animals survived until after VLS4. After 6 h of I/R cardiac output (CO) (p < .001) and mFlux (p < .001) had both decreased. CO increased again after VLS1 (p < .001) and VLS2 (p = .036), whereas mFlux did not change. In contrast, mFlux further decreased after VLS3 (p < .01) and VLS4 (p < .001), whereas CO did not change anymore. Extravascular lung water continued to increase after VLS2 (p = .046) and VLS4 (p = .049). CONCLUSIONS: I/R leads to impaired intestinal microcirculation, which was not restored by volume administration in spite of improved CO. In contrast, further volume administration exceeding preload reserves was associated with additional decreases in the intestinal microcirculation. The potentially negative effect of excessive volume resuscitation after I/R injury should encourage further translational research.

Feasibility Study of a Novel Thoraco-abdominal Aortic Hybrid Device (SPIDER-graft) in a Translational Pig Model.

BACKGROUND: The hybrid SPIDER-graft consists of a proximal descending aortic stent graft and a conventional six branched Dacron graft for open abdominal aortic repair. Technical feasibility with regard to avoiding thoracotomy and extracorporeal circulation (ECC) during thoraco-abdominal aortic hybrid repair and peri-procedural safety of this novel device are unknown. MATERIAL AND METHODS: This was a feasibility and safety study in domestic pigs (75-85 kg). The abdominal aorta including iliac bifurcation, left renal artery, and visceral arteries were exposed via retroperitoneal access. The right iliac branch was first temporarily anastomosed end to side to the distal aorta via partial clamping. During inflow reduction and infra-coeliac cross-clamping, the coeliac trunk (CT) was divided and the proximal stent graft portion of the SPIDER-graft was deployed into the descending aorta via the CT ostium. Retrograde visceral and antegrade aorto-iliac blood flow was maintained via the iliac side branch. The visceral, renal, and iliac arteries were sequentially anastomosed, finally replacing the first iliac end to side anastomosis. Technical success, blood flow, periods of ischaemia, and peri-procedural complications were evaluated after intra-operative completion angiography and post-operative computed tomography angiography. RESULTS: Six animals underwent successful thoracic stent graft deployment and distal open reconstruction without peri-operative death. The median thoracic graft implantation time was 4.5 min, and the median ischaemia times before reperfusion were 10 min for the CT, 8 min for the superior mesenteric artery, 13 min for the right renal artery, and 22 min for the left renal artery. Angiography demonstrated appropriate graft implantation and blood flow measurements confirmed sufficient blood flow through all side branches. CONCLUSION: In this translational pig model, thoraco-abdominal hybrid repair using the novel SPIDER-graft was successful in avoiding thoracotomy and ECC. Technical feasibility and safety appear promising, but need to be reassessed in humans.

Utilization of indocynanine green fluorescent imaging (ICG-FI) for the assessment of microperfusion in vascular medicine.

Intraoperative valuation of organ and tissue microperfusion is always a current topic in different surgical situations. Although indocyanine green fluorescent imaging (ICG-FI) has turned to be a more and more common technique to evaluate organ perfusion, only few studies tried to quantitatively validate the technique for microperfusion assessment. The aim of the following manuscript is to present the results of our interdisciplinary research confirming additional quantitative assessment tools in different surgical conditions. Thus, we are implementing the background-subtracted peak fluorescent intensity (BSFI), the slope of fluorescence intensity (SFI), and the time to slope (TTS) using ICG-FI in several regions of interest (ROI).

Management of acute aortic thrombosis.

Acute aortic thrombosis (AAT) is a rare life threatening event that leads to a sudden occlusion of the aorta. The mortality and morbidity of AAT is still high despite modern surgical techniques. Usually it is the result of a large saddle embolus to the aortic bifurcation, in situ thrombosis of an atherosclerotic aorta or acute occlusion of an abdominal aortic aneurysm. Clinical symptoms depend on the level of the aortic occlusion and can be mistaken for a stroke or similar neurological disease. The combination of age and advanced cardiac disease seems to be significant risks factors for AAT. In patients who have no cardiac or vascular disease this catastrophic event is very rare and is mostly due to hypercoagulable disorders. Revascularization of the ischemic organ/limb as soon as possible is the major aim in the therapy of AAT to avoid further ischemic damage. Surgical reperfusion is the first line approach. If the accepting clinic has no facilities for an immediate surgical intervention it is of primary importance that these patients should be referred to an appropriate center for further management. Paradox seems the fact that most of the patients die as a consequence of reperfusion injury/postperfusion syndrome that occurs after revascularization of acute ischemic limbs.