Nick J. Koning

Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics

The onset of nonpulsatile cardiopulmonary bypass is known to deteriorate microcirculatory perfusion, but it has never been investigated whether this may be prevented by restoration of pulsatility during extracorporeal circulation. We therefore investigated the distinct effects of nonpulsatile and pulsatile flow on microcirculatory perfusion during on-pump cardiac surgery. Patients undergoing coronary artery bypass graft surgery were randomized into a nonpulsatile (n = 17) or pulsatile (n = 16) cardiopulmonary bypass group. Sublingual mucosal microvascular perfusion was measured at distinct perioperative time intervals using sidestream dark field imaging, and quantified as the level of perfused small vessel density and microvascular flow index (vessel diameter < 20 μm). Microcirculation measurements were paralleled by hemodynamic and free hemoglobin analyses. The pulse wave during pulsatile bypass estimated 58 ± 17% of the baseline blood pressure waveform. The observed reduction in perfused vessel density during aorta cross-clamping was only restored in the pulsatile flow group and increased from 15.5 ± 2.4 to 20.3 ± 3.7 mm/mm(2) upon intensive care admission (P < 0.01). The median postoperative microvascular flow index was higher in the pulsatile group [2.6 (2.5-2.9)] than in the nonpulsatile group [2.1 (1.7-2.5); P = 0.001]. Pulsatile flow was not associated with augmentation of free hemoglobin production and was paralleled by improved oxygen consumption from 70 ± 14 to 82 ± 16 ml·min(-1)·m(-2) (P = 0.01) at the end of aortic cross-clamping. In conclusion, pulsatile cardiopulmonary bypass preserves microcirculatory perfusion throughout the early postoperative period, irrespective of systemic hemodynamics. This observation is paralleled by an increase in oxygen consumption during pulsatile flow, which may hint toward decreased microcirculatory heterogeneity during extracorporeal circulation and preservation of microcirculatory perfusion throughout the perioperative period.

Changes in Microcirculatory Perfusion and Oxygenation During Cardiac Surgery With or Without Cardiopulmonary Bypass

From the Anesthesiology and Cardiothoracic Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. Address reprint requests to Christa Boer, Department of Anesthesiology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands. E-mail: c.boer@vumc.nl

Microcirculatory Perfusion Is Preserved During Off-Pump but Not On-Pump Cardiac Surgery

OBJECTIVE This study investigated the perioperative course of microcirculatory perfusion in off-pump compared with on-pump surgery. Additionally, the impact of changes in systemic hemodynamics, hematocrit, and body temperature was studied. DESIGN Prospective, nonrandomized, observational study. SETTING Tertiary university hospital. PARTICIPANTS Patients undergoing coronary artery bypass grafting with (n = 13) or without (n = 13) use of cardiopulmonary bypass. INTERVENTIONS Microcirculatory measurements were obtained at 5 time points ranging from induction of anesthesia to ICU admission. MEASUREMENTS AND MAIN RESULTS Microcirculatory recordings were performed with sublingual sidestream dark field imaging. Despite a comparable reduction in intraoperative blood pressure between groups, the perfused vessel density decreased more than 20% after onset of extracorporeal circulation but remained stable in the off-pump group. The reduction in microvascular perfusion in the on-pump group was further paralleled by decreased hematocrit and temperature. Although postbypass hematocrit levels and body temperature were restored to similar levels as in the off-pump group, the median microvascular flow index remained reduced after bypass (2.4 [2.3-2.7]) compared with baseline (2.8 [2.7-2.9]; p = 0.021). CONCLUSIONS Microcirculatory perfusion remained unaltered throughout off-pump surgery. In contrast, microvascular perfusion declined after initiation of cardiopulmonary bypass and did not recover in the early postoperative phase.

Side-by-Side Alterations in Glycocalyx Thickness and Perfused Microvascular Density During Acute Microcirculatory Alterations in Cardiac Surgery.

Endothelial glycocalyx injury causes microcirculatory perfusion disturbances in experimental studies, but the relevance in a clinical setting remains unknown. We investigated whether glycocalyx dimensions are reduced after onset of CPB and whether this is associated with alterations in microvascular perfusion.

Impaired microcirculatory perfusion in a rat model of cardiopulmonary bypass: the role of hemodilution

Although hemodilution is attributed as the main cause of microcirculatory impairment during cardiopulmonary bypass (CPB), this relationship has never been investigated. We investigated the distinct effects of hemodilution with or without CPB on microvascular perfusion and subsequent renal tissue injury in a rat model. Male Wistar rats (375-425 g) were anesthetized, prepared for cremaster muscle intravital microscopy, and subjected to CPB (n = 9), hemodilution alone (n = 9), or a sham procedure (n = 6). Microcirculatory recordings were performed at multiple time points and analyzed for perfusion characteristics. Kidney and lung tissue were investigated for mRNA expression for genes regulating inflammation and endothelial adhesion molecule expression. Renal injury was assessed with immunohistochemistry. Hematocrit levels dropped to 0.24 ± 0.03 l/l and 0.22 ± 0.02 l/l after onset of hemodilution with or without CPB. Microcirculatory perfusion remained unaltered in sham rats. Hemodilution alone induced a 13% decrease in perfused capillaries, after which recovery was observed. Onset of CPB reduced the perfused capillaries by 40% (9.2 ± 0.9 to 5.5 ± 1.5 perfused capillaries per microscope field; P < 0.001), and this reduction persisted throughout the experiment. Endothelial and inflammatory activation and renal histological injury were increased after CPB compared with hemodilution or sham procedure. Hemodilution leads to minor and transient disturbances in microcirculatory perfusion, which cannot fully explain impaired microcirculation following cardiopulmonary bypass. CPB led to increased renal injury and endothelial adhesion molecule expression in the kidney and lung compared with hemodilution. Our findings suggest that microcirculatory impairment during CPB may play a role in the development of kidney injury.

Relationship between Sensory Stimulation and Side Effects in Percutaneous Radiofrequency Treatment of the Trigeminal Ganglion.

The objective of this study was to determine the efficacy of percutaneous radiofrequency (RF) treatment of the trigeminal ganglion for treating patients with trigeminal neuralgia, to determine which patients have a long‐term benefit, and to evaluate the effect of RF parameters.

Endothelial hyperpermeability after cardiac surgery with cardiopulmonary bypass as assessed using an in vitro bioassay for endothelial barrier function

BACKGROUND The mechanisms causing increased endothelial permeability after cardiopulmonary bypass (CPB) have not been elucidated. Using a bioassay for endothelial barrier function, we investigated whether endothelial hyperpermeability is associated with alterations in plasma endothelial activation and adhesion markers and can be attenuated by the use of pulsatile flow during CPB. METHODS Patients undergoing cardiac surgery were randomized to non-pulsatile (n=20) or pulsatile flow CPB (n=20). Plasma samples were obtained before (pre-CPB) and after CPB (post-CPB), and upon intensive care unit (ICU) arrival. Changes in plasma endothelial activation and adhesion markers were determined by enzyme-linked immunosorbent assay. Using electric cell-substrate impedance sensing of human umbilical vein endothelial monolayers, the effects of plasma exposure on endothelial barrier function were assessed and expressed as resistance. RESULTS Cardiopulmonary bypass was associated with increased P-selectin, vascular cell adhesion molecule-1, and von Willebrand factor plasma concentrations and an increase in the angiopoietin-2 to angiopoietin-1 ratio, irrespective of the flow profile. Plasma samples obtained after CPB induced loss of endothelial resistance of 21 and 23% in non-pulsatile and pulsatile flow groups, respectively. The negative effect on endothelial cell barrier function was still present with exposure to plasma obtained upon ICU admission. The reduction in endothelial resistance after exposure to post-CPB plasma could not be explained by CPB-induced haemodilution. CONCLUSION The change in the plasma fingerprint during CPB is associated with impairment of in vitro endothelial barrier function, which occurs irrespective of the application of a protective pulsatile flow profile during CPB. CLINICAL TRIAL REGISTRATION NTR2940.

Reduction of vascular leakage by imatinib is associated with preserved microcirculatory perfusion and reduced renal injury markers in a rat model of cardiopulmonary bypass

Background: Cardiopulmonary bypass during cardiac surgery leads to impaired microcirculatory perfusion. We hypothesized that vascular leakage is an important contributor to microcirculatory dysfunction. Imatinib, a tyrosine kinase inhibitor, has been shown to reduce vascular leakage in septic mice. We investigated whether prevention of vascular leakage using imatinib preserves microcirculatory perfusion and reduces organ injury markers in a rat model of cardiopulmonary bypass. Methods: Male Wistar rats underwent cardiopulmonary bypass after treatment with imatinib or vehicle (n=8 per group). Cremaster muscle microcirculatory perfusion and quadriceps microvascular oxygen saturation were measured using intravital microscopy and reflectance spectroscopy. Evans Blue extravasation was determined in separate experiments. Organ injury markers were determined in plasma, intestine, kidney, and lungs. Results: The onset of cardiopulmonary bypass decreased the number of perfused microvessels by 40% in the control group [9.4 (8.6–10.6) to 5.7 (4.8–6.2) per microscope field; P<0.001 vs baseline], whereas this reduction was not seen in the imatinib group. In the control group, the number of perfused capillaries remained low throughout the experiment, whilst perfusion remained normal after imatinib administration. Microvascular oxygen saturation was less impaired after imatinib treatment compared with controls. Imatinib reduced vascular leakage and decreased fluid resuscitation compared with control [3 (3–6) vs 12 ml (7–16); P=0.024]. Plasma neutrophil‐gelatinase‐associated‐lipocalin concentrations were reduced by imatinib. Conclusions: Prevention of endothelial barrier dysfunction using imatinib preserved microcirculatory perfusion and oxygenation during and after cardiopulmonary bypass. Moreover, imatinib‐induced protection of endothelial barrier integrity reduced fluid‐resuscitation requirements and attenuated renal and pulmonary injury markers.

The effects of pulsatile cardiopulmonary bypass on microcirculatory perfusion: perspectives from a null-result study.

In their recent study, Elbers et al1 showed that pulsatile flow does not alter human microvascular perfusion during cardiopulmonary bypass (CPB). The authors are to be praised for focusing on direct visualization of the microcirculation during pulsatile CPB because previous studies suggest that the benefit of pulsatile over nonpulsatile CPB lies in the small vasculature. To our knowledge, this is also the first clinical study that describes the energy-equivalent pressure, a quantification of pulsatility. However, there are several arguments to believe that the absent benefit of pulsatile flow on microcirculatory perfusion as concluded by the authors is unsubstantiated. Unpublished findings by our group show that pulsatile flow preserves microcirculatory perfusion after CPB, but this effect commences after CPB and is continuous in the early postoperative period. We believe that the authors may have missed the beneficial effects of pulsatility because of the short time span of microcirculatory visualization used in their study. Moreover, the presumable nonpulsatile flow as described by the authors generates a low mean pulse pressure of 7 mmHg. Historically, the discussion about pulsatile flow during CPB has always been limited because of a lack of quantification studies and different definitions of nonpulsatile and pulsatile flow.2,3 Although some auhors propose a pulse pressure cutoff point of 15 mmHg to nduce beneficial effects on organ perfusion and outcome, it annot be ruled out that the nonpulsatile flow as described by he authors may have exhibited pulsatile benefits.2 Therefore, he authors investigated pulsatile flow in a dose-response maner rather than comparing nonpulsatile and pulsatile CPB. We lso suggest that the detection of subtle differences in microirculatory vessel density should be made by identification and nalysis of every single vessel rather than using grid crossings s has earlier been described for fast-track analysis.4,5 Finally, the crossover design and short observation frame limit the value of the results. The lack of baseline measurements hinders conclusions about the first sequence of the allocated perfusion mode. In particular, the first microcirculatory measurements were performed during 1 specific perfusion mode, whereas subsequent measurements were performed after a combination of the 1st and 2nd perfusion modes. This suggests that the 2nd measurement comprises a mixture of the effects of both flow modalities on microcirculatory perfusion. Moreover, we hypothesize that endothelial shear stress, a reduction in proinflammatory proteins, and hemorheologic changes might be involved in the beneficial effects of pulsatile flow. In this context, a longer period of observation should be implemented. In conclusion, the combination of the previously mentioned discussion points may have resulted in an unfounded null-result onclusion by the authors. To draw firm conclusions about the ffects of pulsatile flow on microcirculatory perfusion, we ould like to suggest that Elbers et al consider the use of a oncrossover design with baseline measurements that allows omparison of total nonpulsatile flow with pulsatile flow during he entire aortic cross-clamp period and a longer follow-up of icrocirculatory observations.

Anterior Cervical Osteophytes and Sympathetic Hyperactivity in Patients with Tinnitus: Size Matters

Context: Pathological changes secondary to degeneration of the cervical intervertebral disc may cause irritation of sympathetic nerve fibers, leading to sympathetic symptoms and tinnitus. Objectives: The aim of this study was to relate the effect of percutaneous radiofrequency treatment of superior cervical sympathetic ganglion in patients with tinnitus to cervical pathology. Method: A retrospective study of 74 consecutive patients who underwent treatment of the superior cervical sympathetic ganglion for tinnitus that persisted for 1 month or longer from October 2016 to January 2018. The work-up of a patient with tinnitus consisted of a standardized clinical history, a bilateral audiogram and a cervical spine radiograph. Results: All patients had a test blockade of superior cervical sympathetic ganglion first, and 54% of these patients (n=40) responded with a reduction of their tinnitus. These patients underwent a radiofrequency lesion and 53% (n=21) responded with a reduction of their tinnitus at 7 weeks following treatment. The size of anterior osteophyte at the fifth cervical vertebrae was related to a positive response at 7 weeks following this treatment. Patients with tinnitus and an anterior osteophyte at vertebrae C5 more than 17% of the width of those vertebrae had a success rate of 52% following treatment of the superior cervical sympathetic ganglion, compared to 13%, when the anterior osteophyte at C5 was 17% or less. Conclusions: The size of anterior cervical osteophytes is associated with a higher success rate of radiofrequency lesions of the superior sympathetic ganglion for tinnitus. The current results imply a role for cervical sympathetic nervous system irritation in the development of tinnitus in a subgroup of patients.