The impact of fluid optimisation before induction of anaesthesia on hypotension after induction.

Intra-operative hypotension is a known predictor of adverse events and poor outcomes following major surgery. Hypotension often occurs on induction of anaesthesia, typically attributed to hypovolaemia and the haemodynamic effects of anaesthetic agents. We assessed the efficacy of fluid optimisation for reducing the incidence of hypotension on induction of anaesthesia. This prospective trial enrolled 283 patients undergoing radical cystectomy and randomly allocated them to goal-directed fluid therapy (n = 142) or standard fluid therapy (n = 141). Goal-directed fluid therapy patients received fluid optimisation based on stroke volume response to passive leg raise before induction; those with positive passive leg raise received intravenous crystalloid fluid boluses until stroke volume was optimised. Baseline mean arterial pressure was measured on the morning of surgery and on arriving in the operating theatre. This post-hoc analysis defined haemodynamic instability as either a > 30% relative drop in mean arterial pressure compared with baseline or absolute mean arterial pressure < 55 mmHg, within 15 min of induction. Forty-two (30%) goal-directed fluid therapy patients underwent fluid optimisation after finding an intravascular fluid deficit via passive leg raise testing; 106 (75%) goal-directed fluid therapy and 112 (79%) standard fluid therapy patients met criteria for haemodynamic instability. There was no significant difference in the incidence of haemodynamic instability between the goal-directed fluid therapy and standard fluid therapy groups using absolute mean arterial pressure drop below 55 mmHg (p = 0.58) or using pre-surgical testing or pre-surgical mean arterial pressure values as baseline (p = 0.21, p = 0.89, respectively); however, the difference in the incidence of haemodynamic instability was significant using the operating theatre baseline mean arterial pressure (p = 0.004). We conclude that fluid optimisation before induction of general anaesthesia did not significantly impact haemodynamic instability.

Hypothermia attenuates NO production in anesthetized rats with endotoxemia.

Sepsis is often associated with upregulation of nitric oxide production and fever, and it is common to control an excessive febrile response with antipyretic therapy and external cooling. Our aim was to evaluate the effect of hypothermia on NO production in a model of septic shock. Rats were anesthetized, ventilated, and instrumented for hemodynamic monitoring and divided into four groups. Normothermic controls (NC) received saline intravenously and were maintained at 37 °C. Hypothermic controls (HC) received saline but were allowed to become hypothermic. Normothermic endotoxic (NE) received Escherichia Coli lipopolysaccharides (LPS) intravenously to induce endotoxic shock and was maintained at 37 °C. Hypothermic endotoxic (HE) received LPS intravenously and was allowed to become hypothermic. Exhaled NO (NOe) was measured from mixed expired gas at time zero and every 30 min, for 5 h. After injection of LPS, NOe increased substantially in the NE group (700 ± 24 ppb), but increased only to 25 ± 2 ppb in the HE group. NOe increased to 90 ± 3 ppb in the NC group, and to 17.6 ± 3.1 ppb in the HC group after 5 h (P < 0.05), whilst blood pressure remained stable. In the HE group, blood pressure fell immediately after injection of the LPS, but thereafter remained stable despite the rise in NOe. In the NE group, the blood pressure fell gradually, and the animals became hypotensive. During the natural course of endotoxemia in anesthetized rats, allowing severe hypothermia to ensue by not actively managing temperature and hemodynamics resulted in significantly reduced expired NO concentrations, lung injury, and prolonged survival. The clinical benefits of such a finding currently remain unclear and merit further investigation.

Nitric oxide plays a minimal role in hypoxic pulmonary vasoconstriction in isolated rat lungs.

The goal of this study was to elucidate the importance of nitric oxide production during hypoxic pulmonary vasoconstriction (HPV). One group of Sprague Dawley rats received an ip injection of saline (controls), while a second group received an ip injection of Escherichia coli lipopolysacharides (LPS-treated) to render them septic. Three hours later, the animals were anesthetized and prepared for the isolated lung experiment. The lungs were ventilated and perfused with diluted autologous blood (Hct 23%) at constant flow rate while monitoring pulmonary arterial pressure (Pa). Nitric oxide production from the lungs was monitored by measuring its concentration in the mixed exhaled gas (NOe) offline. NOe in the isolated lungs was 2 ppb in controls and 90 ppb in the LPS treated lungs. Hypoxia caused Pa to rise from 10 to 17 mmHg in control lungs, and from 10 to 27 mmHg in the LPS treated lungs. NO production was then manipulated to determine if it affects HPV. NOe was increased by adding L-arginine to the blood, and was blocked by adding nitro-L-arginine (LNA). L-Arginine had minimal effect on NOe in control lungs, but increased NOe in LPS treated lungs, and yet HPV was similar in the 2 groups. Despite inhibition of NO synthesis with nitro-L-arginine (LNA), HPV was potentiated equally in control and in LPS treated lungs (Pa rose by 23 mmHg). Thus NO production did not affect the difference in HPV between control and LPS treated lungs. The results suggest that NO does not plays a primary role in HPV.

Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats.

We investigated the pathogenic mechanism(s) of small intestinal injury during acidosis in relation to circulating nitric oxide (NO) in an experimental rat model. Rats were anesthetized, paralyzed, and mechanically ventilated with room air. Hydrochloric acid (0.16 mmol bolus followed by 0.132 mmol/kg/h) was infused through the jugular vein for 5 hours. Control rats received a saline infusion. Arterial blood gases, blood pressure, and blood pH were measured every 30 minutes. The involvement of NO in this acidosis model was assessed by measuring plasma concentration of nitrite/nitrate (NOx) and by evaluating inducible NO synthase (iNOS) expression in small intestinal mucosa. Intestinal injury was assessed by measuring myeloperoxidase (MPO) activity, thiobarbituric acid reactants (TBARS), and histologic scores. HCl infusion was associated with hypotension, decreased blood pH, increased plasma concentration of NOx, augmented intestinal mucosal iNOS expression, MPO activity, TBARS, and histopathologic injury scores. Pretreatment with an iNOS inhibitor, aminoguanidine (AG, 50 mg/kg), reversed HCl-induced hypotension without a change in blood pH. HCl-induced lesions, MPO activity, TBARS, and plasma NOx production were decreased by AG. Our data show that the pathogenic mechanisms of acidosis-induced small intestinal lesions involve up-regulation of NO production by increased expression of iNOS and augmentation of superoxide radicals and MPO activity.

Acidosis stimulates nitric oxide production and lung damage in rats.

Systemic hypotension during sepsis is thought to be due to nitric oxide (NO) overproduction, but it may also be due to acidosis. We evaluated in healthy rats the consequences of acid infusion on NO and blood pressure. Sprague-Dawley rats were anesthetized, and ventilated with room air. The animals were randomized into four groups. Group 1 (C, n = 10) received only normal saline at rates comparable to the other groups. Group 2 (A1, n = 10) received hydrochloric acid at 0.162 mmol in the first 15 to 30 min, followed by a continuous infusion of 0.058 mmol/h for 5 h. Group 3 (AG+A1, n = 6) was pretreated with aminoguanidine (AG, 50 mg/kg), and HCl was infused as above. Group 4 (A2, n = 7) received HCl at twice the rate used in A1. Nitric oxide concentration in the exhaled gas (ENO), blood gases, and mean arterial pressure were measured every 30 min. Acid infusion in A1 caused the pH to fall gradually from 7.43 +/- 0. 01 to 7.13 +/- 0.05. This moderate decrease in pH was associated with a marked increase in ENO (1.6 +/- 0.3 to 114.2 +/- 22.3 ppb), an increase in plasma nitrite/nitrate (17.3 +/- 3.7 to 35.2 +/- 4.3 microM), and a significant decrease in blood pressure (110.5 +/- 6.3 to 63.3 +/- 15.0 mm Hg). Furthermore, acidosis caused lung inflammation, as suggested by the increase in lung myeloperoxidase activity (282.2 +/- 24.7 to 679.3 +/- 57.3 U/min/g) and lung injury score (1.7 +/- 0.2 to 3.5 +/- 0.6). Acidosis after AG pretreatment was associated with a similar change in pH, but the increase in ENO, nitrite/nitrate, and systemic hypotension were prevented. Furthermore, lung injury was attenuated by AG, as suggested by a lower myeloperoxidase activity, though lung injury score was not altered. In this model, moderate acidosis causes increases in NO, hypotension, and lung inflammation. Lung inflammation and injury are due in part to acidosis and NO production. This is the first report to show a direct effect of chronic acidosis on NO production and lung injury. These results have profound implications on the role of acidosis on NO production and lung injury during sepsis.

The effects of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia.

UNLABELLED: We investigated the effects of body mass index (BMI) on functional residual capacity (FRC), respiratory mechanics (compliance and resistance), gas exchange, and the inspiratory mechanical work done per liter of ventilation during general anesthesia. We used the esophageal balloon technique, together with rapid airway occlusion during constant inspiratory flow, to partition the mechanics of the respiratory system into its pulmonary and chest wall components. FRC was measured by using the helium dilution technique. We studied 24 consecutive and unselected patients during general anesthesia, before surgical intervention, in the supine position (8 normal subjects with a BMI < or = 25 kg/m2, 8 moderately obese patients with a BMI >25 kg/m2 and <40 kg/m2, and 8 morbidly obese patients with a BMI > or = 40 kg/m2). We found that, with increasing BMI: 1. FRC decreased exponentially (r = 0.86; P < 0.01) 2. the compliance of the total respiratory system and of the lung decreased exponentially (r = 0.86; P < 0.01 and r = 0.81; P < 0.01, respectively), whereas the compliance of the chest wall was only minimally affected (r = 0.45; P < 0.05) 3. the resistance of the total respiratory system and of the lung increased (r = 0.81; P < 0.01 and r = 0.84; P < 0.01, respectively), whereas the chest wall resistance was unaffected (r = 0.06; P = not significant) 4. the oxygenation index (PaO2/PAO2) decreased exponentially (r = 0.81; P < 0.01) and was correlated with FRC (r = 0.62; P < 0.01), whereas PaCO2 was unaffected (r = 0.06; P = not significant) 5. the work of breathing of the total respiratory system increased, mainly due to the lung component (r = 0.88; P < 0.01 and r = 0.81; P < 0.01, respectively). In conclusion, BMI is an important determinant of lung volumes, respiratory mechanics, and oxygenation during general anesthesia with patients in the supine position. IMPLICATIONS: The aim of this study was to investigate the influence of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia.

Neutrophil sequestration in the lung following acute aortic occlusion starts during ischaemia and can be attenuated by tumour necrosis factor and nitric oxide blockade.

OBJECTIVES: To investigate the role of lower extremity ischaemia in acute lung injury with special emphasis on the role of tumour necrosis factor (TNF) and nitric oxide (NO) as mediators of neutrophil (PMN) chemotaxis in the lung. DESIGN: Prospective randomised study. MATERIALS AND METHODS: Sprague-Dawley rats were randomized into four groups: group 1 (x-clmap): aorta clamped just above the bifurcation for 3 h; group 2 (AG): 50 mg/kg aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor, was administered prior to aortic occlusion; group 3 (Steroids): 1 mg/kg dexamethasone was administered prior to aortic occlusion; and group 4 (TNFbp): 2 mg/kg TNFbp, a PEGylated dimeric form of the high affinity TNF receptor I (R1) was administered prior to aortic occlusion to block TNF action. Groups 2, 3 and 4 were subjected to the same ischaemia time as group 1. NO concentration in the exhaled gas (ENO) was measured in 30 min intervals. At the end of the 3 h ischaemia, one lung was excised and fixed for routine histological evaluation, and the other underwent bronchoalveolar lavage (BAL). PMN chemotaxis towards the BAL fluid was then measured using the blindwell technique. RESULTS: ENO in group 1 increased from 0.9 +/- 0.3 ppb at baseline, to 41.3 +/- 9.2 ppb at the end of ischaemia. Animals in this group exhibited significant lung inflammation. Aminoguanidine, dexamethasone and TNFbp blocked NO production (peak ENO values of 7.2 +/- 1.9, 12.6 +/- 1.3 and 8.9 +/- 1.7 ppb for groups 2, 3 and 4 respectively), decreased PMN chemotaxis and sequestration in the lung, and attenuated lung inflammation. CONCLUSIONS: Acute lung injury resulting from distal aortic occlusion starts during ischaemia. TNF and NO blockade decrease PMN chemotaxis and sequestration and attenuate the lung injury process.

Determination of cardiac output during mechanical ventilation by electrical bioimpedance or thermodilution in patients with acute lung injury: effects of positive end-expiratory pressure.

OBJECTIVE: To evaluate the usefulness of transthoracic electrical bioimpedance in sedated and paralyzed patients with acute lung injury during mechanical ventilation with and without early application of positive end-expiratory pressure (PEEP). DESIGN: Prospective, repeated-measures study. SETTING: University-affiliated intensive care center. PATIENTS: Ten patients with acute lung injury. INTERVENTIONS: Simultaneous, three-paired cardiac output (CO) measurements by transthoracic electrical bioimpedance (TEB) and thermodilution (TD) were made at 0 and 15 cm H2O of PEEP. MEASUREMENTS AND MAIN RESULTS: The average of the TD-CO measurements was 7.22 +/- 2.12 (SD) L/min during 0 cm H2O of positive end-expiratory pressure (ZEEP), and 6.91 +/- 1.72 L/min during PEEP (NS). The average of the TEB-CO measurements was 4.48 +/- 1.37 L/min during ZEEP, and 6.03 +/- 2.03 L/min during PEEP (p < .05). For each level of PEEP, bias and precision between methods were calculated. Bias calculations between TD-CO and TEB-CO ranged from -1.54 +/- 7.02 L/min at ZEEP to -2.52 +/- 4.28 L/ min at PEEP, and -2.47 +/- 6.09 L/min for mixed data at ZEEP and PEEP. There was no significant correlation between the percent change with PEEP in TEB-CO and TD-CO (r2 =.05, NS). CONCLUSIONS: In patients with acute lung injury: a) the agreement between TEB-CO and TD-CO measurements is poor; b) agreement is not clinically improved by application of PEEP; and c) TEB cannot monitor trends in CO.

Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes?

To assess the possible differences in respiratory mechanics between the acute respiratory distress syndrome (ARDS) originating from pulmonary disease (ARDSp) and that originating from extrapulmonary disease (ARDSexp) we measured the total respiratory system (Est,rs), chest wall (Est,w) and lung (Est,L) elastance, the intra-abdominal pressure (IAP), and the end-expiratory lung volume (EELV) at 0, 5, 10, and 15 cm H2O positive end-expiratory pressure (PEEP) in 12 patients with ARDSp and nine with ARDSexp. At zero end-expiratory pressure (ZEEP), Est,rs and EELV were similar in both groups of patients. The Est,L, however, was markedly higher in the ARDSp group than in the ARDSexp group (20.2 +/- 5.4 versus 13.8 +/- 5.0 cm H2O/L, p < 0.05), whereas Est,w was abnormally increased in the ARDSexp group (12.1 +/- 3.8 versus 5.2 +/- 1.9 cm H2O/L, p < 0.05). The IAP was higher in ARDSexp than in ARDSp (22.2 +/- 6.0 versus 8.5 +/- 2.9 cm H2O, p < 0.01), and it significantly correlated with Est,w (p < 0. 01). Increasing PEEP to 15 cm H2O caused an increase of Est,rs in ARDSp (from 25.4 +/- 6.2 to 31.2 +/- 11.3 cm H2O/L, p < 0.01) and a decrease in ARDSexp (from 25.9 +/- 5.4 to 21.4 +/- 55.5 cm H2O/L, p < 0.01). The estimated recruitment at 15 cm H2O PEEP was -0.031 +/- 0.092 versus 0.293 +/- 0.241 L in ARDSp and ARDSexp, respectively (p < 0.01). The different respiratory mechanics and response to PEEP observed are consistent with a prevalence of consolidation in ARDSp as opposed to prevalent edema and alveolar collapse in ARDSexp.

Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide.

OBJECTIVE: To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis. DESIGN: Prospective, randomized, controlled study on anesthetized animals. SETTING: A cardiopulmonary research laboratory. SUBJECTS: Forty-seven male adult Sprague-Dawley rats. INTERVENTIONS: Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 1 ppm inhaled nitric oxide (LNA+NO, n=7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n=7). Inhaled NO was administered continuously until the end of the experiment. MEASUREMENTS AND MAIN RESULTS: Systemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9+/-1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant after 180 mins (58.9+/-16.6 ppb) and reached 95.3+/-27.5 ppb after 5 hrs (p< .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension, which lasted for the duration of the experiment. LNA reversed systemic hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidosis, and decreased the mortality rate (from 55% to 29%). CONCLUSIONS: In this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.

Role of nitric oxide and tumor necrosis factor on lung injury caused by ischemia/reperfusion of the lower extremities.

PURPOSE: Acute aortic occlusion with subsequent ischemia/reperfusion (I/R) of the lower extremities is known to predispose to lung injury. The pathophysiologic mechanisms of this injury are not clear. In the present study, we studied the role of tumor necrosis factor (TNF) and nitric oxide (NO) in lung injury caused by lower extremity I/R. METHODS: A rat model in which the infrarenal aorta was cross-clamped for 3 hours followed by 1 hour of reperfusion was used. The rats were randomized into five groups: group 1, aorta exposed but not clamped; group 2, aorta clamped for 3 hours, followed by 1 hour of reperfusion; group 3, 1 mg/kg dexamethasone administered before the aorta was clamped; group 4, 25 mg aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor, administered before the aorta was clamped; and group 5, 2 mg/kg TNFbp, a PEG-ylated dimeric form of the high-affinity p55 TNF receptor I (RI), administered before the aorta was clamped. NO concentration in the exhaled gas (ENO) was measured, as an index of NO production by the lung, in 30 minute intervals during I/R. Serial arterial blood samples for TNF assay were obtained during the course of the experiment. At the end of the experiment, the lungs were removed and histologically examined for evidence of injury. RESULTS: ENO in group 2 increased from 0.7 +/- 0.3 ppb at baseline to 54.3 +/- 7.5 ppb at the end of ischemia and remained stable during reperfusion (54.6 +/- 8.5 ppb at the end of reperfusion). ENO production was blocked by aminoguanidine, by dexamethasone, and by TNFbp given before aortic occlusion. Serum TNF in groups 2, 3 and 4 increased rapidly during early ischemia, reaching its peak value 60 minutes after occlusion of the aorta, then gradually declined to baseline levels at the end of ischemia, and remained low during reperfusion. TNFbp decreased serum TNF concentration significantly when it was given before aortic occlusion. Histologic examination of the lungs at the end of the experiment revealed that aminoguanidine, dexamethasone, and TNFbp had a protective effect on the lungs. CONCLUSIONS: Serum TNF increases rapidly during lower extremity ischemia and causes increased production of NO from the lung by upregulating iNOS. Increased NO is associated with more severe lung injury, and iNOS blockade has beneficial effects on the lung. TNF blockade before ischemia decreases NO production by the lung and attenuates lung injury. ENO can be used as an early marker of lung injury caused by lower extremity I/R.