Christopher Beck

Hypercapnic Acidosis Preserves Gastric Mucosal Microvascular Oxygen Saturation in a Canine Model of Hemorrhage.

The authors aimed to clarify the effects of hypercapnic acidosis and its timing on gastric mucosal oxygenation in a canine model of hemorrhage. This was designed as a prospective, controlled, randomized animal study set in a university research laboratory. Five chronically instrumented dogs were used. Dogs were repeatedly anesthetized (sevoflurane 1.5 MAC), mechanically ventilated, and randomized to each of the following protocols. In a control series (CON), animals underwent hemorrhage during normoventilation (etCO2, 35 mmHg). In a second series, hypercapnia (etCO2, 70 mmHg) was applied before onset of hemorrhage (prophylactic hypercapnia), whereas in the third series, hypercapnia was applied after hemorrhage (therapeutic hypercapnia, THE). Microvascular oxygenation (&mgr;HbO2) of the gastric mucosa was continuously assessed by tissue reflectance spectrophotometry. Cardiac output was continuously measured, and oxygen delivery (DO2) was intermittently calculated. In CON, hemorrhage decreased DO2 (from 11 ± 3 mL·kg−1·min−1 to 8 ± 2 mL·kg−1·min−1 and 8 ± 2 mL·kg−1·min−1 after 30 and 75 min, respectively) and &mgr;HbO2 (from 57% ± 4% to 43% ± 11% and 50% ± 11%). Prophylactic hypercapnia attenuated the effects of hemorrhage on DO2 (12 ± 2 mL·kg−1·min−1 to 10 ± 2 mL·kg−1·min−1 and 11 ± 2 mL·kg−1·min−1) and preserved &mgr;HbO2 (52% ± 3% to 47% ± 5% and 57% ± 3%). Initial effects of hemorrhage in THE were comparable to CON (DO2 from 11 ± 2 mL·kg−1·min−1 to 8 ± 1 mL·kg−1·min−1; &mgr;HbO2 from 56% ± 7% to 43% ± 9%), but after application of hypercapnic acidosis, baseline levels were restored (DO2 10 ± 3 mL·kg−1·min−1; &mgr;HbO2 52% ± 14%). Hypercapnic acidosis applied before or after hemorrhage (THE) preserves microvascular mucosal oxygenation. If these experimental findings may be transferred to the clinical setting, deliberate hypercapnic acidosis could serve to augment oxygenation of the splanchnic region in states of compromised circulation, e.g., hemorrhage.

Acute, short-term hypercapnia improves microvascular oxygenation of the colon in an animal model of sepsis.

INTRODUCTION The deterioration of microcirculatory oxygenation of the gut plays a vital role in the development of sepsis. Acute hypercapnia enhances the microcirculatory oxygenation of the splanchnic region under physiological conditions, while the effect of hypercapnia under sepsis is unknown. The aim of this study was to investigate the effects of acute hypercapnia and hypercapnic acidosis on the colonic microcirculation and early cytokine response in polymicrobial sepsis. METHODS Experiments were performed on 103 male Wistar rats. Colon ascendens stent peritonitis (CASP) surgery with varying stent diameters was conducted to establish a moderate polymicrobial sepsis model. In a second series, 24h of sepsis development induced by CASP surgery was followed by 120min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO2 45±5mmHg) or moderate hypercapnic ventilation targets (pCO2 75±5mmHg) via exogenous carbon dioxide application. The effect of acidosis was investigated by metabolically buffering the hypercapnic acidosis with tromethamine. Microcirculatory oxygenation of the colon wall (tissue reflectance spectrophotometry) and hemodynamic variables were recorded continuously and arterial blood gas and cytokine (TNF-α, IL-6, IL-10) levels were analyzed intermittently. RESULTS In septic animals the microcirculatory oxygenation of the colon deteriorated under normocapnia (-7.0±7.6% at 90min) but was maintained under hypercapnic acidosis (+3.6±7.6%) and buffered hypercapnia (+1.5±4.4%). Cytokine levels were significantly higher in septic animals as opposed to sham animals but did not differ between normocapnic and hypercapnic groups. CONCLUSIONS Acute hypercapnic acidosis and buffered hypercapnia both improve splanchnic microcirculatory oxygenation in a septic animal model, thereby counteracting the adverse effect induced by sepsis. The circulating pro- and anti-inflammatory cytokine levels are not modulated after 120min of hypercapnia.

Vasopressin V1A receptors mediate the increase in gastric mucosal oxygenation during hypercapnia

Hypercapnia (HC) improves systemic oxygen delivery (DO₂) and microvascular hemoglobin oxygenation of the mucosa (μHbO₂). Simultaneously, HC increases plasma levels of vasopressin. Although vasopressin is generally regarded a potent vasoconstrictor particularly in the splanchnic region, its effects on splanchnic microcirculation during HC is unclear. The aim of this study was to evaluate the role of endogenous vasopressin on gastric mucosal oxygenation and hemodynamic variables during physiological (normocapnia) and hypercapnic conditions. Five dogs were repeatedly anesthetized to study the effect of vasopressin V(1A) receptor blockade ([Pmp¹,Tyr(Me)²]-Arg⁸-Vasopressin, 35  μg/kg) on hemodynamic variables and μHbO₂ during normocapnia or HC (end-tidal CO₂ 70  mmHg). In a control group, animals were subjected to HC alone. μHbO₂ was measured by reflectance spectrophotometry, systemic DO₂ was calculated from intermittent blood gas analysis, and cardiac output was measured by transpulmonary thermodilution. Data are presented as mean±s.e.m. for n=5 animals. During HC alone, DO₂ increased from 12±1 to 16±1 ml/kg per min and μHbO₂ from 70±4 to 80±2%. By contrast, additional vasopressin V(1A) receptor blockade abolished the increase in μHbO₂ (80±2 vs. 69±2%) without altering the increase in DO₂ (16±1 vs. 19±2  ml/kg per min). Vasopressin V1A receptor blockade (VB) during normocapnia neither affected DO₂ (13±1 vs. 14±1  ml/kg per min) nor μHbO₂ (75±3 vs. 71±5%). Vasopressin V(1A) receptor blockade abolished the increase in μHbO₂ during HC independent of DO₂. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate the increase in gastric microcirculatory mucosal oxygenation induced by acute HC.

Neither inhalative nor intravenous application of carbon monoxide modifies gastric mucosal oxygenation.

This study was designed to compare the effects of different ways of administering carbon monoxide (intravenous and inhalative) on gastric mucosal oxygenation in a canine model of hemorrhage. Six chronically instrumented dogs were repeatedly anesthetized and randomized to each of the following protocols: In a first series the animals were ventilated either with 100 ppm carbon monoxide (CO) or without followed by hemorrhage and re-transfusion. In a second series a saturated CO solution was infused, compared to normal saline, again followed by hemorrhage and re-transfusion. In a control series, animals received either CO-saline or saline without any further intervention. Microvascular oxygenation of the gastric mucosa (µHbO2) was assessed continuously by tissue reflectance spectrophotometry. Cardiac output was measured intermittently and oxygen delivery (DO2) was calculated. The application of CO, inhalative and intravenous, increased carboxyhemoglobin levels without effect on µHbO2. Hemorrhage reduced µHbO2 in all groups, paralleled by a reduction in DO2 without any differences between groups related to the application of CO. Neither intravenous nor inhalative application of CO alters µHbO2 during physiological conditions or during hemorrhage. Thus, independent of the application way, low dose CO does not seem to modulate regional mucosal oxygenation in cytoprotective concentrations.

Perioperative liver protection.

Purpose of reviewThis review presents important pathophysiological alterations associated with impaired liver function and discusses protective perioperative strategies and the various anaesthetic agents recommended. Recent findingsPerioperative liver impairment is a serious complication of anaesthesia and surgery. Unfortunately, clinicians are provided with only crude macrohaemodynamic monitoring devices to optimize their therapy. Technical improvements have revealed some complex mysteries of perioperative microcirculatory alterations and have disclosed a large heterogeneity between different vascular beds. The present review will critically discuss current clinical concepts of optimizing global haemodynamic variables and the often contrasting effects of vasoactive agents on the microcirculatory nutritional blood flow. Finally, promising protective experimental interventions of pharmacological or ischaemic preconditioning are presented and their often disillusioning transition into recent clinical trials is highlighted. SummaryTargeted perioperative liver protection still lacks adequate monitoring tools and is currently based on optimization of global haemodynamic variables. While there is currently no evidence suggesting a positive effect of ischaemic preconditioning, promising experimental results of pharmacological preconditioning and therapeutic hypothermia require further evaluation in larger randomized clinical trials.

The beneficial effects of acute hypercapnia on microcirculatory oxygenation in an animal model of sepsis are independent of K+ATP channels

BACKGROUND Acute hypercapnia maintains the microcirculatory oxygenation of the splanchnic region during sepsis. The first aim of this study was to characterize the role of K(+)ATP channels on the microcirculatory flow and oxygenation during acute moderate hypercapnia. The second aim was to investigate whether a short period of hypercapnia induces detrimental effects in an otherwise undamaged rodent lung. METHODS Experiments were performed on 60 male Wistar rats. A moderate polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) surgery. 24h after induction of sepsis volume-controlled and pressure-limited ventilation was established for 120 min, with either normocapnic (pCO2 35-45 mmHg) or moderate hypercapnic ventilation targets (pCO2 65-75 mmHg) and with or without non-selective K(+)ATP channel blockade with glibenclamide. Microcirculatory blood flow of the colonic wall as well as oxygen delivery and consumption were assessed with tissue laser Doppler and reflectance spectrophotometry. Hemodynamic variables were recorded and plasma cytokine levels and myeloperoxidase levels of the lungs were analyzed. RESULTS In septic animals microcirculatory oxygenation deteriorated progressively with normocapnia (-11.7 ± 11.8%) but was maintained (-2.9 ± 5.6%) with hypercapnia. This effect was associated with an increased microcirculatory oxygen consumption in septic animals with normocapnia (+25.7 ± 37.1%) that was decreased in the hypercapnia groups (-7.2 ± 28.1%). The effect of hypercapnia in septic animals was not altered by additional K(+)ATP channel blockade (-5.7 ± 32.7%). Hypercapnia neither induced an inflammatory response in lungs nor altered the systemic cytokine response. CONCLUSIONS The observed beneficial effect of hypercapnia on microvascular oxygenation of the colon in sepsis does not seem to be mediated via K(+)ATP channels.

Hypothermia Improves Oral and Gastric Mucosal Microvascular Oxygenation during Hemorrhagic Shock in Dogs

Hypothermia is known to improve tissue function in different organs during physiological and pathological conditions. The aim of this study was to evaluate the effects of hypothermia on oral and gastric mucosal microvascular oxygenation (μHbO2) and perfusion (μflow) under physiological and hemorrhagic conditions. Five dogs were repeatedly anesthetized. All animals underwent each experimental protocol (randomized cross-over design): hypothermia (34°C), hypothermia during hemorrhage, normothermia, and normothermia during hemorrhage. Microcirculatory and hemodynamic variables were recorded. Systemic (DO2) and oral mucosal (μDO2) oxygen delivery were calculated. Hypothermia increased oral μHbO2 with no effect on gastric μHbO2. Hemorrhage reduced oral and gastric μHbO2 during normothermia (−36 ± 4% and −27 ± 7%); however, this effect was attenuated during additional hypothermia (−15 ± 5% and −11 ± 5%). The improved μHbO2 might be based on an attenuated reduction in μflow during hemorrhage and additional hypothermia (−51 ± 21 aU) compared to hemorrhage and normothermia (−106 ± 19 aU). μDO2 was accordingly attenuated under hypothermia during hemorrhage whereas DO2 did not change. Thus, in this study hypothermia alone improves oral μHbO2 and attenuates the effects of hemorrhage on oral and gastric μHbO2. This effect seems to be mediated by an increased μDO2 on the basis of increased μflow.

Vasopressin V1A receptors mediate the stabilization of intestinal mucosal oxygenation during hypercapnia in septic rats.

BACKGROUND Microvascular oxygen saturation (μHBO2) plays an essential role in the development and outcome of sepsis. Hypercapnia (HC) improves the microvascular oxygenation of the mucosa in both healthy and septic animals. Vasopressin V1A receptor blockade prevents this positive effect under otherwise physiological conditions. The aim of this study was to investigate the effects and mechanisms of the vasopressin system during hypercapnia under septic conditions. METHODS 80 rats were randomized into 8 groups (N=10). Colon ascendens stent peritonitis (CASP) or sham surgery was performed on 40 animals each to establish a moderate polymicrobial sepsis or sham control, respectively. 24h after sepsis induction the animals were subjected to 120min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO2 35-45mmHg) or moderate hypercapnic (pCO2 of 65-75mmHg) ventilation targets. Animals received either vasopressin V1A receptor blockade (SR 49059, 1mgkg(-1) i.v.) or vehicle solution (dimethyl sulfoxide, 1%). Blood pressure, heart rate, pO2 and pCO2 were measured and microcirculatory oxygenation (μHBO2) and microcirculatory flow (μflow) were recorded using tissue reflectance spectrophotometry. Oxygen supply (μDO2) and consumption (μVO2) were calculated from intermittent blood gas analysis. RESULTS In septic animals, μHBO2 declined during normocapnia (-11±10.3) but remained unchanged during hypercapnia. μHBO2 declined with vasopressin V1A receptor blockade both during normocapnia (-7.4±10.6) and hypercapnia (-9.2±9.8). Microcirculatory oxygen consumption was significantly reduced by hypercapnia in septic animals (-2.4·10(5) [AU]±2.4·10(5) [AU]). In sham animals, μHBO2 and μVO2 did not change. CONCLUSION Vasopressin V1A receptors mediate the beneficial effects of hypercapnia on microcirculatory oxygenation during sepsis. The effects of vasopressin on μHBO2 might be related to decreased oxygen consumption during hypercapnia.

Evaluation of a new side-stream, low dead space, end-tidal carbon dioxide monitoring system in rats

The aim of this study was to evaluate a newly developed infrared side-stream capnograph with minimal sample volume for the continuous measurement of end-tidal carbon dioxide (CO2) concentrations in small rodents. Thirty-four male Wistar rats (weight 345 ± 70 g) were treated in accordance with the National Institutes of Health (NIH) guidelines for animal care. All experiments were performed with approval of the local animal care and use committee. Sepsis was induced by implanting an 18 gauge stent into the colon 24 h prior to the experiments, allowing a constant fecal leakage into the peritoneal cavity (25 septic and nine control animals). Hemodynamic variables and end-tidal CO2 were recorded continuously and arterial blood (5 × 120 µL) was sampled periodically for arterial blood gas analysis. After baseline controlled mechanical ventilation was randomized and titrated to either normocapnia (35–45 mmHg) or hypercapnia (65–75 mmHg) with exogenous application of CO2. A total of 155 paired CO2 measurements comparing end-tidal and arterial partial pressure were conducted. Side-stream capnography underestimated the CO2 partial pressure with a bias of −6.1 mmHg and a 95% limit of agreement from 6.7 to –19.1 mmHg. Our results suggest that side-stream end-tidal CO2 monitoring with a low dead space could be utilized in rats as a surrogate for the arterial CO2 measurement over a wide range of partial pressures in normal and septic animals.

Endogenous nitric oxide reduces the efficacy of the endothelin system to maintain blood pressure during high epidural anaesthesia in conscious dogs

Background and objective: During high epidural anaesthesia, endothelin only contributes minimally to blood pressure stabilization. This phenomenon could result from the inhibitory action of nitric oxide on the endothelin system. To clarify this, we studied the interaction between nitric oxide and endothelin during high epidural anaesthesia in conscious dogs, in comparison to the interaction of nitric oxide and vasopressin. Methods: Six animals were used in 45 individual experiments randomly arranged as follows: N‐ω‐nitro‐arginine‐methylester 0.3–10 mg kg−1 under physiological conditions or during high epidural anaesthesia (lidocaine 1%) and N‐ω‐nitro‐arginine‐methylester (l‐NAME) 0.3–10 mg kg−1 after preceding endothelin (Tezosentan®) or vasopressin (&bgr;‐mercapto‐&bgr;,&bgr;‐cyclo‐penta‐methylene‐propionyl‐O‐Me‐Tyr‐Arg‐vasopressin) receptor blockade under physiological conditions or during high epidural anaesthesia. During control experiments normal saline was injected either intravenously (n = 5) or into the epidural space (n = 4). Results: N‐ω‐nitro‐arginine‐methylester increased mean arterial pressure dose‐dependently in all groups. However, this effect was substantially reduced in the presence of the endothelin receptor antagonist compared to N‐ω‐nitro‐arginine‐methylester alone, both under control conditions (7 ± 3 vs. 21 ± 3 mmHg; P < 0.05) and during high epidural anaesthesia (17 ± 3 vs. 30 ± 1 mmHg; P < 0.05). Blockade of vasopressin showed no similar relationship with N‐ω‐nitro‐arginine‐methylester. Conclusions: The diminished increase in mean arterial pressure after injection of N‐ω‐nitro‐arginine‐methylester only during endothelin receptor blockade indicates that endogenous nitric oxide inhibits the action of endothelin during high epidural anaesthesia and might thus explain the reduced efficacy of endothelin in maintaining blood pressure during high epidural anaesthesia.