Effect of l-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL-8, TNFα and nitrite/nitrate in human septic shock

Objectives: We tested the effects of N^G-nitro-L-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, on plasma levels of interleukin (IL) IL-6, IL-8, tumor necrosis factor-alpha (TNFα) and nitrite/nitrate (NO ₂ ^? /NO ₃ ^? ) in patients with severe septic shock. Design: Prospective clinical study. Setting: Surgical intensive care unit at a university hospital. Patients: 11 consecutive patients with severe septic shock. Interventions: Standard hemodynamic measurements were made and blood samples taken at intervals before, during, and after a 12-h infusion of l-NAME 1 mg · kg^?1 ·h^?1 for determination of plasma IL-6, IL-8, TNFα and NO ₂ ^? /NO ₃ ^? concentration. Measurements and results: Patients with sepsis had increased plasma levels of IL-6, IL-8, TNFα, and NO ₂ ^? /NO ₃ ^? (p<0.05). Plasma levels of IL-6, IL-8, and NO ₂ ^? /NO ₃ ^? were negatively correlated with systemic vascular resistance (r=?0.62, r=?0.65, and r=?0.78, respectively, all p<0.05). Continuous infusion of l-NAME increased mean arterial pressure and systemic vascular resistance, with a concomitant reduction in cardiac output (all p<0.01). No significant changes were seen in levels of plasma IL-6, IL-8, and NO ₂ ^? /NO ₃ ^? during the 24-h observation period. Plasma levels of TNFα were significantly reduced during l-NAME infusion compared to baseline (p<0.05). Conclusions: NO plays a role in the cardiovascular derangements of human septic shock. Inhibition of NO synthesis with l-NAME does not promote excessive cytokine release in patients with severe sepsis.     

An 18oxygen inhalation method for determination of total body formation of nitric oxide in humans

The formation of nitric oxide (NO) and the subsequent conversion of the NO formed into nitrate require molecular oxygen. Based on this fact, we have recently developed a method using inhalation of the stable oxygen isotope, i.e. ¹⁸O₂, to determine total formation of NO in small laboratory animals. The method has now been further developed to be applicable also in humans. Five healthy awake male subjects inhaled a gas mixture of unlabelled and 18-labelled oxygen (approximate ratio 4:1) in nitrogen from a closed breathing system equipped with eliminators for carbon dioxide and water vapour. The ratio of unlabelled to 18-labelled oxygen, as well as the total oxygen concentration during the inhalation, were monitored. Venous blood samples were taken before and after the inhalation for analysis of unlabelled and ¹⁸O-labelled nitrate by gas chromatography/mass spectrometry. The procedure was repeated with the same protocol on a later occasion, during ongoing treatment with the NO synthesis inhibitor N^G-monomethyl- L -arginine ( L -NMMA). The average nitrate level in plasma in the absence of L -NMMA was 26 μmol l^–1. The rate of total synthesis of NO was estimated to be 0·38 ± 0·06 μmol kg^–1 h^–1, corresponding to a total body formation of 600–700 μmol/24 h in an adult male. Infusion of L -NMMA caused an increase in mean arterial blood pressure from 86 ± 4 to 99 ± 5 mmHg (P<0·05). The average plasma level of nitrate during infusion of L -NMMA was 24 μmol l^–1. NO formation during infusion of L -NMMA was 0·17 ± 0·03 μmol kg^–1 h^–1, i.e. significantly (P<0·05) lower than in the absence of L -NMMA. We suggest that the described method allows direct determination of total NO formation in man. The method may be useful in the study of various experimental and pathophysiological conditions affecting NO formation.     

Role of thromboxane,prostaglandins and leukotrienes in endotoxic and septic shock

Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB₂ and 6-keto-PGF₁ in a large number of species. A smaller, delayed and more prolonged increase in TxB₂ and 6-keto-PGF₁ are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA₂ exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB₂ and 6-keo-PGF₁ concentrations in patients with septic shock, and elevated LTD₄ in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered.     

Differential inducible nitric oxide synthase activity in circulating neutrophils vs. mononuclears of septic shock patients

Objective: To compare nitric oxide synthase (NOS) activity in circulating neutrophils and mononuclear cells of patients with septic shock to healthy subjects.Design and setting: Prospective study in the general intensive care unit (30 beds) of a university affiliated-hospital and the A.C. Burton Vascular Biology Research Laboratory.Patients: Six septic patients and seven healthy volunteers.Measurements and results: We measured NOS in circulating neutrophils and mononuclears. Constitutive (cNOS) and inducible (iNOS) activities were analyzed by the [³H]l-arginine-l-citrulline assay. Plasma NO_x^– was determined by chemiluminescence. NO_x^– was higher in septic vs. controls (median 110, IQR 39–250 vs. 23, 14–46 µM; p<0.05). cNOS in septic cells was unmeasurable. iNOS in septic neutrophils was higher (median 34.9, IQR 10.4–95.8 vs. controls 2.5, 0–2.7 U; p<0.05) while iNOS in septic mononuclears was unaltered (median 16.4, IQR 9.1–52.6 vs. controls 8.9, 5.9–20.3 U; p=0.240).Conclusions: Increased iNOS activity was found in circulating neutrophils of septic shock patients compared to healthy volunteers. Moreover, differential iNOS activity was evident in circulating neutrophils vs. mononuclears of patients with septic shock. Further investigations are warranted to confirm this differential iNOS activity and to explore its significance     

Nitric oxide production is enhanced in patients with heat stroke

Objective: To determine whether nitric oxide (NO) production is increased in heat stroke (HS) patients. Design: A prospective analysis of nitrite and nitrate (NO^· ₂/NO₃) levels in ten HS patients was performed at the HS center in Makkah, Saudi Arabia. Methods: Plasma (NO^· ₂/NO₃) levels were determined spectrophotometrically before cooling (0 time), and at 6, 12, and 24 h post-cooling. Results: The mean level of NO in the ten HS victims before cooling was significantly higher than in eight control patients (35.6 ± 37.0 vs 3.0 ± 4.2 μmol/l; p < 0.01). The levels were higher in non-survivors than in survivors. NO also correlated positively with the Acute Physiology and Chronic Health Evaluation II score (r = 0.72, p < 0.018). There was no correlation between the NO level before cooling and blood pressure, rectal temperature, or cooling time. Conclusion: HS is associated with excessive NO production, the magnitude of which is proportional to the severity of illness. NO may be an important mediator and integral part of the pathophysiological processes resulting in HS and may be a central factor linking the neurological and cardiovascular abnormalities observed in HS. Received: 15 May 1998 Final revision received: 21 September 1998 Accepted: 22 October 1998     

Effects of NO inhalation on pulmonary leukocyte sequestration and blood volume in porcine endotoxaemia

Objective: Sequestration and migration of activated neutrophils plays a major role in the pulmonary injury typical of septic shock and the adult respiratory distress syndrome. Inhaled NO may counteract alveolar-capillary damage attributed to activated neutrophils. The present study describes a method to directly demonstrate the effects of NO inhalation on endotoxin-induced sequestration of ^{99 m}Tc-labelled leukocytes [A_s(t)] in the lungs of pigs.¶Design: Prospective controlled study.¶Setting: Laboratory for experimental surgery at a university medical centre.¶Subjects: Anaesthetised and ventilated pigs.¶Interventions: To induce inflammatory shock 26 animals received a continuous endotoxin infusion. Thirteen animals inhaled NO from the start of the experiments, while 13 served as controls. In 13 animals from both groups, leukocytes were labelled in vitro and reinjected, while in the 13 others erythrocytes were labelled in vivo to provide corrections for changes in blood volume.¶Measurements and results: The pulmonary distribution of ^{99 m}Tc-labelled leukocytes or erythrocytes was studied dynamically for 180 min. After correction for changes in pulmonary and heart blood volume (PBV, HBV), leukocyte sequestration curves were generated. Endotoxin induced pulmonary vasoconstriction, reduced PBV, impaired oxygenation, and caused a maximum increase in A_s(t) of 30 % in the lungs. NO inhalation attenuated pulmonary vasoconstriction and the reduction in PBV. The maximum increase in A_s(t) was reduced to 15 % of baseline.¶Conclusions: Inhaled NO exerts its main vascular effects in the pulmonary microvasculature, the primary site of physiological neutrophil margination and pathological adhesion of activated leukocytes. Early use of NO inhalation may offer protection against the development of more lasting pulmonary failure in septic shock by reducing leukocyte sequestration in the lungs.     

Nitric oxide indices in human septic shock

OBJECTIVES: To study the relation between nitrite, nitrate, nitrotyrosine, and nitrosothiols as NO indices in human septic shock. DESIGN: A prospective clinical study. SETTING: Intensive care units in a university hospital and a central county hospital. PATIENTS: Sixteen patients admitted for septic shock. Nine healthy volunteers served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with septic shock had a hyperdynamic circulatory response and required infusion of at least two vasopressors to maintain systemic blood pressure. Four episodes of recurrent shock occurred in two patients. Heparinized plasma was collected once daily for analysis of NO indices. Peak plasma concentrations of nitrite + nitrate (NOx) were elevated in first episodes of septic shock; 144+/-39 microM vs. controls, 20+/-3 microM (p < .05). Peak plasma NOx concentrations in recurrent shocks were; 160+/-19 microM. Peak plasma concentrations of 3-nitrotyrosine (NT) were elevated in primary septic shock 102+/-19 pmol x mL(-1) vs. controls 14+/-6 pmol x mL(-1) (p < .05). Peak NT concentrations were 117+/-37 pmol x mL(-1) in recurrent septic shock. Peak plasma NT concentrations did not coincide with peak NOx concentrations in half of the episodes of septic shock. Plasma NT was elevated (59+/-15 pmol x mL(-1) vs. controls 14+/-6 pmol x mL(-1), p < .05) in patients with normal plasma NOx concentrations throughout septic shock. Plasma concentrations of nitrosothiols did not change during septic shock. CONCLUSIONS: Plasma concentrations of NOx and NT are elevated in primary episodes of septic shock and may also be elevated in secondary septic shock, but too few episodes of recurrent septic shock occurred to allow firm conclusions. Plasma concentrations of NT are elevated in patients with septic shock with normal plasma NOx concentrations, indicating that plasma concentrations of NOx may not always accurately reflect NO production. Reactive nitrogen species may be formed in septic shock, and measuring both NOx and NT may give a better indication of NO production in septic shock than NOx alone. Plasma levels of nitrosothiols did not change during septic shock.     

Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition

Objective Decreased diaphragmatic contractility and organ failure observed during sepsis is mediated by an overproduction of nitric oxide (^.NO)-derived species, mitochondria being a major target of oxidative and nitrative stress. We tested the potential protective effects of (a) a novel synthetic antioxidant, the manganese(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP⁵⁺) and (b) the inducible ^.NO synthase inhibitor aminoguanidine (AG) on a rat model of sepsis.Setting University research laboratories.Subjects and interventions Sepsis was induced by cecal ligation and perforation in rats.Measurements and results Systemic hemodynamics, pulmonary gas exchange, in vitro diaphragmatic function and mitochondrial respiration were evaluated. Moreover, plasma and mitochondrial oxidative and nitrative stress parameters were investigated. Sepsis determined diaphragmatic dysfunction and a significant decrease in mitochondrial coupling and respiration. Oxidative stress was evidenced by decreased plasma antioxidants and increased lipid oxidation. Tyrosine nitration was increased in the plasma and mitochondria of the septic animals. These alterations were ameliorated or prevented by either MnTE-2-PyP⁵⁺ or AG.Conclusions Our results demonstrate that overproduction of ^.NO and ^.NO-derived reactive species play a critical role in mitochondrial impairment and diaphragmatic function during sepsis. More importantly, AG but mainly the novel metalloporphyrin MnTE-2-PyP⁵⁺ were able to ameliorate diaphragmatic and mitochondrial dysfunction and could contribute to preventing organ failure during severe sepsis.This work was supported in part by FOGARTY-NIH, Wellcome Trust and Guggenheim Foundation for Homero Rubbo and Rafael Radi, and the Howard Hughes Medical Institute for Rafael Radi, and by PRONBIO, Fundación Manuel Pérez for Nicolás Nin.     

Platelet-activating factor and phospholipase A2 in patients with septic shock and trauma

Objective To study blood and bronchoalveolar lavage (BAL) fluid levels of platelet activating factor (PAF-acether) and phospholipase A₂ (PLA₂) in patients with septic shock or following severe trauma.Design Prospective controlled clinical study.Setting An intensive care unit (ICU) of a university hospital.Patients and participants The study comprised 12 patients, 8 with septic shock and 4 with trauma, consecutively admitted to the ICU. Healthy volunteers were used as controls.Measurements and results Blood PAF-acether and plasma PLA₂ levels were measured within 24 h after the patients arrival to the ICU. The Apache II score and outcome were registered. Median values for PAF-acether and PLA₂ in the septic shock patients were 10.5×10^–10 M and 5300 units/ml, respectively, whereas corresponding values in the trauma patients were 1.3×10^–10M and 770 units/ml. Normal healthy individuals had no detectable PAF-acether in the circulating blood (<0.5×10^–10 M), and normal plasma PLA₂ activity was <300 units/ml. Moreover, both PLA₂ and PAF-acether levels correlated well with the severity of the disease as assessed by the Apache II scoring system (p<0.01 for PLA₂ andp<0.05 for PAF-acether). In addition, PAF-acether and PLA₂ were determined in BAL fluid of patients with septic shock (n=5) and trauma (n=3); increased PAF-acether levels were found in four patients with septic shock and one patient with trauma.Conclusion These results demonstrate a significant increase of both PLA₂ and PAF-acether in the circulation of trauma patients, and a further increase in septic shock patients. It is possible that PAF-acether and PLA₂ can be used as markers for the severity of the disease in septic shock and following severe trauma.This work was supported by grant B91-17x-05983-11C from the Swedish Medical Research Council and by a grant from Östergötlands Läns Landsting     

Prognostic values of serum cytokines in septic shock

Objective

To prospectively evaluate the prognostic values of two serum cytokine levels, TNFα and IL 6 serially measured at predetermined intervals in septic shock patients unresponsive to correction of hypoxaemia and plasma volume expansion and treated according to a strict protocol designed to meet specific therapeutic goals (goal-directed therapy). The evolution of serum lactate levels and oxygen-derived parameters was also investigated.

Design

A prospective case series study. Patients were followed-up until they were discharged from the hospital, or died.

Setting

ICU of a university hospital.

Patients

30 consecutive patients with septic shock of various origins.

Interventions

The therapy was aimed at achieving and maintaining for at least 24 h supranormal values CI (≥4.01·min^?1·m^?2), oxygen delivery (DO₂≥550ml· min^?1·m^?2) and oxygen uptake (VO₂≥150ml·min^?1· m^?2) using a combination of fluid loading, norepinephrine, dobutamine and dopamine. A significant decrease in TNFα levels was associated with a favourable outcome while TNFα levels remained elevated in the patients who died in shock or of multiple organ failure. No prognostic value was associated with changes in IL 6 concentrations. In a stepwise logistic regression analysis, only TNFα levels contributed significantly to prediction of patients' outcome. A significant decrease in serum lactate concentrations was observed both in survivors and in patients who survived the episode of septic shock, but subsequently died of multiple organ failure. A positive DO₂/VO₂ relationship was observed only in survivors but did not contribute significantly to prediction of patient outcome.

Conclusions

TNFα is a major mediator involved in the pathogenesis of septic shock and its decrease was significantly associated with a favourable outcome. IL 6 is certainly involved in the pathophysiology of septic shock but further studies are required to determine whether or not it is directly involved in the mediation of late and lethal complications of septic shock. Serum lactate levels and oxygen-derived variables were of less interest as prognostic factors.     

Is nitric oxide overproduction the target of choice for the management of septic shock?

Sepsis is a heterogeneous class of syndromes caused by a systemic inflammatory response to infection. Septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs, and is a leading cause of patient mortality in intensive care units. Despite important advances in understanding its pathophysiology, therapy remains largely symptomatic and supportive. A decade ago, the overproduction of nitric oxide (NO) had been discovered as a potentially important event in this condition. As a result, great hopes arose that the pharmacological inhibition of NO synthesis could be developed into an efficient, mechanism-based therapeutic approach. Since then, an extraordinary effort by the scientific community has brought a deeper insight regarding the feasibility of this goal. Here we present in summary form the present state of knowledge of the biological chemistry and physiology of NO. We then proceed to a systematic review of experimental and clinical data, indicating an up-regulation of NO production in septic shock; information on the role of NO in septic shock, as provided by experiments in transgenic mice that lack the ability to up-regulate NO production; effects of pharmacological inhibitors of NO production in various experimental models of septic shock; and relevant clinical experience. The accrued evidence suggests that the contribution of NO to the pathophysiology of septic shock is highly heterogeneous and, therefore, difficult to target therapeutically without appropriate monitoring tools, which do not exist at present.     

Validation of a simple method assessing nitric oxide and nitrogen dioxide concentrations

Monitoring of nitric oxide (NO) and nitrogen dioxide (NO₂) is a prerequisite for the clinical use of NO. Chemiluminescence, the reference method, cannot be used as a routine in clinical practice in view of its cost and other restraints. This study was performed to evaluate a device using an electrochemical method (Polytrons NO and NO₂, Dräger^®). Forty-nine simultaneous measurements of NO and various oxides of nitrogen (NO_x) concentrations by the two apparatus were performed. NO measurements by means of these two methods are very well correlated (r=0.96;p<^10–5). The mean difference according to the method of Bland and Altman was 2.8±1.7 ppm, with the limits of agreement at –0.6 and +6.2 ppm (confidence interval of 95%). There was also a good correlation between measurements of NO₂ obtained via Polytrons and NO_x via chemiluminescence (r=0.84;p<10^–5). However, NO₂ measurements obtained via Polytron may be insufficient to exclude potential toxicity of NO₂ due to the inability to detect measurements in the ppbrange. This study demonstrates that devices designed for industrial purposes (Polytrons NO and NO₂, Dräger^®) can be used for clinical purposes.     

A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine,an inhibitor of the nitric oxide synthetase

N^G-monomethyl-L-arginine (L-NMMA) is an inhibitor of the enzyme nitric-oxide-synthetase. Nitric oxide (NO), produced by endothelial and vascular cells regulates physiological vascular tone, blood pressure and tissue perfusion via guanylate-cyclase and cGMP. In an advanced stage of therapy resistant septic shock in response to inflammatory mediators, NO is overproduced. This leads to vasodilatation, a fall in systemic blood pressure and an attenuated vasoconstriction-response to sympathetic-stimuli. Two episodes of severe and prolonged hypotension in a patient with sepsis were successfully treated twice by bolus therapy of L-NMMA within 4 weeks. On both occasions blood pressure was reversed to normal and the continuous use of high doses of catecholamines were stopped. In contrast to the immediate response of blood pressure, heart rate and central venous pressure remained stable. Cardiac output dropped to 68% and PaO₂ increased. These findings indicate that NO-synthetase-inhibitors may be of value in the therapy of human septic shock.     

Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin-2

Abstract Hypotension is a dose-limiting side effect of interleukin-2 (IL-2) therapy. This may be due to increased biosynthesis of the potent vasodilator nitric oxide (NO) induced by cytokines such as tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which are known to be generated during IL-2 therapy. We describe the relationship between NO biosynthesis and changes in immunological and vascular parameters during IL-2 therapy in 13 patients with metastatic cancer. Plasma concentrations of neopterin and nitrite plus nitrate (NO_x) were higher in cancer patients prior to treatment compared with normal subjects (neopterin; 10·8±1·4 vs. 2·0±0·4 ng ml^-1, P<0·001: NO_x; 45±6 vs. 28±2 μM, P<0·005). Pretreatment TNF-α and IFN-γ plasma concentrations were not significantly different in cancer patients from those in controls. During infusion of IL-2 (18 times 10⁶ international units m^-2 per day for 5 days) these parameters increased, reaching maximal concentrations at day 3 for IFN-γ and day 5 for TNF-α, neopterin and NO_x. The maximal induced NO_x correlated with maximal TNF-α (r = 0·60, P<0·04), IFN-γ (r = 0·63, P<0·02) and neopterin (r = 0·66, P<0·01). As plasma NO_x concentrations increased, systolic blood pressure fell, reaching a minimum at day 3 despite a continued rise in NO_x concentrations. These changes were accompanied by a continuous increase in pulse rate throughout the infusion period. These findings indicate that induction of NO biosynthesis contributes to hypotension induced during IL-2 therapy. Inhibitors of NO synthase may be useful in limiting toxicity, thus allowing administration of higher and possibly more efficacious doses of this cytokine in the treatment of cancer.     

Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock

Objective The aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of thel-arginine nitric oxide pathway, in patients with septic shock.Design A prospective, open, single-dose study.Setting The medical ICU of a university hospital.Patients Six patients with severe septic shock.Interventions Complete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg^–1). Arterial pressure was then monitored during the next 24 h or until death.Measurements and results Methylene blue increased the mean arterial pressure from 69.7±4.5 to 83.7±5.1 mmHg (p=0.028) and the mean pulmonary artery pressure, from 34.3±7.2 to 38.7±8.0 mmHg (p=0.023). Systemic vascular resistance index was increased from 703.1±120.6 to 903.7±152.2 dyne.s.cm^–5.m^–2 (p=0.028) and pulmonary vascular resistance index, from 254.6±96.9 to 342.2±118.9 dyne.s.cm^–5.m^–2 (p=0.027). The PaO₂/FIO₂ decreased from 229.2±54.4 to 162.2±44.1 mmHg (p=0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO₂, VO₂, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2–3 h. All but one patients died, three in shock and two in multiple organ failure.Conclusions MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.The study was supported by the Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris     

Knee area tissue oxygen saturation is predictive of 14-day mortality in septic shock

Purpose

Thenar eminence tissue oxygen saturation (StO₂) was developed to assess organ perfusion. However, mottling, a strong predictor of mortality in septic shock, develops preferentially around the knee. We aimed to evaluate the prognostic value of StO₂ measured around the knee in septic shock patients and compare it to thenar StO₂.

Methods

This was a prospective observational study in a tertiary teaching hospital. All consecutive patients with septic shock were included. Parameters were recorded when vasopressors were started (H0) and every 6?h during 24?h. Their predictive value was assessed on 14-day mortality.

Results

Fifty-two patients were included. SOFA score was 11 (9–15) and SAPS II was 56 (40–72). At 6?h after ICU admission (H6), mean arterial pressure, cardiac index, and central venous pressure were not different between non-survivors and survivors; but non-survivors had higher arterial lactate level (8.8?±?5.0 vs. 2.2?±?1.5?mmol/l, P?P?2 (62?±?20 vs. 72?±?9?%, P?=?0.03). At H6, StO₂ was lower in non-survivors; this difference was not significant for thenar StO₂ (70?±?15 vs. 77?±?12?%, P?=?0.10) but was very pronounced for knee StO₂ (39?±?23 vs. 71?±?12?%, P?2 was associated with a higher mottling score (P?P?R ²?=?0.2), and a lower urinary output (P?=?0.02, R ²?=?0.12).

Conclusion

After initial septic shock resuscitation, StO₂ measured around the knee is a strong predictive factor of 14-day mortality.     

Nitrogen monoxide and carbon monoxide transfer interpretation: state of the art

Just a few clinicians routinely measure the subcomponents of the lung diffusing capacity for Carbone monoxide (DL_CO). This is because the measurement of membrane and blood conductances for CO (Dm_CO and Db_CO = θ_CO × V_c, respectively) by the classic Roughton and Forster method is complicated and time consuming. In addition, it mistakenly assumes a close relationship between alveolar oxygen partial pressure (PAO₂) and mean intracapillary oxygen partial pressure (PcapO₂) which is the true determinant of specific conductance of haemoglobin for CO (θ_CO). Besides that, the critical multistep oxygenation method along with different linear equations relating 1/θ_CO to PcapO₂ gave highly scattered Dm_CO and V_c values. The Dm and V_c can also be derived from a simultaneous measurement of DL_NO and DL_CO with the blood resistance for NO assumed to be negligible. However, recent in vitro and in vivo experiments point towards a finite value of θ_NO (about 4·5 ml_NO × ml_blood^?1 × min^?1 × mmHg^?1). Putting together the arguments and our clinical data allows us to report here the state of the art in partitioning the CO diffusing capacity into its constitutive components, with the goal to encourage further studies examining the sensitivity of Dm_CO and V_c to alterations observed in parenchymal diseases.     

Peripheral vascular resistance in septic shock: its relation to outcome

To support the concept that patients who die of septic shock have a persistent defect in peripheral vascular tone irrespective of cardiac index (CI), a retrospective study was undertaken of 42 patients with documented septic shock. From the patient records, the single lowest CI (t=2) measured after initial values (t=1) with concomitantly obtained haemodynamic and metabolic variables was taken. Group 1 consisted of 21 survivors and group 2 of 21 patients, who had died in shock. Initial haemodynamic and metabolic variables were comparable between the groups, reflecting shock with a hyperdynamic circulation and lactic acidemia. At t=2, median CI measured 3.21·min^-1·m^-2 in both groups, but mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) were higher in group 1 than 2 (p<0.0005). Changes in arterial blood lactate levels also differed significantly. The rankcorrelation between CI and SVRI at t=2 was significant in group 1 (r _s=-0.69, p<0.005) but not in group 2 (r _s=-0.34). Our data suggest that when CI decreases in septic shock, patients with a fatal outcome have less capability to augment vascular resistance than survivors. Hence, peripheral vascular failure, even if complicated by inability to maintain an elevated CI, may be a major haemodynamic determinant of mortality in septic shock.     

The metabolic fate of long-term inhaled nitric oxide

The fate of inhaled nitric oxide (NO) has not been precisely defined in critically ill patients. This study aimed at defining the effects of long-term NO inhalation on circulating NO byproduct levels. During NO therapy, plasma and urine from 13 critically ill patients were sampled daily for determination of the stable byproducts of NO (nitrite [NO₂⁻] and nitrate [NO₃⁻]. Routine monitoring data included inhaled NO concentration, hemodynamic parameters, arterial blood gases, creatinine clearance, and C-reactive protein. For the first 24 hours of NO inhalation (6.3 ± 1.1 ppm), NO₃⁻ plasma concentration increased (from 13.3 ± 5.4 to 52.3 ± 17.6 μmol/L), but NO₂⁻ plasma concentration was not affected. The NO₃⁻ plasma concentration was correlated with the C-reactive protein level, the inhaled NO concentration. Renal excretion of NO metabolites was unaltered by NO inhalation. The N0₃ concentrations returned to baseline when NO therapy was discontinued. Long-term NO inhalation was associated with a consistent increase in the NO₃⁻ plasma concentration. NO byproducts may be implicated in the systemic effects associated with this treatment.     

A comparison between the acute effects of nitric oxide synthase inhibition and fluid resuscitation on myocardial function and metabolism in entotoxemic dogs

:Nitric oxide (NO) synthase inhibitors increase mean arterial pressure (MAP) and systemic vascular resistance (SVR) in animal models of sepsis and in humans with septic shock. However, NO synthese inhibitors may cause coronary vessel constriction leading to myocardial ischemia and increased mortality in endotoxemic animals. This study was designed to test the acute effect of N^G-nitro- -arginine (L-NAME) on left ventricular (LV) function and coronary blood flow in a dog model of endotoxemia. :In open chest, anesthetized dogs endotoxemia was induced intravenously (IV) by Escherichia coli lipopolysaccharide at 2 mg/ kg for 60 minutes. This resulted in hypotension, acidosis, and decreased SVR while cardiac index (CI) was maintained. When MAP was ≤60 mm Hg, animals were resuscitated with either dextran (group I), or L-NAME 30 mg/kg IV bolus (group II). Group III received L-NAME only. A fourth group of dogs was given endotoxin and not resuscitated. Animals were followed up for 30 minutes after intervention. Animals in the fourth group were followed up until the MAP was approximately 30 mm Hg. Heart rate, Cl, MAP, LV end systolic and diastolic pressures, dP/dt at a pressure of 40 mm Hg, left anterior descending artery coronary blood flow, regional LV contraction (sonomicrometer crystals), coro nary pressures, gas tension, and lactates were continuously recorded. A catheter placed in the coronary sinus allowed measurement of coronary sinus pressure, as well as coronary sinus lactate and gas tensions. Stroke volume index, stroke work index, systemic vascular resistance index (SVRI), coronary vascular resistance, percent myocardial shortening, myocardial oxygen consumption (Mvo2) and net myocardial lactate production were calculated. :In Group I, fluid administration increased MAP, stroke work index, coronary blood flow, percent myocardial shortening, and MvoZ. In Group II, L-NAME increased MAP to the same extent as fluid administration without evidence of coronary ischemia or myocardial dysfunction. L-NAME did not alter MVo₂ in either endotoxemic or nonendotoxemic animals. In group III, L-NAME alone resulted in a significant increase in MAP and SVRI, but its effects on coronary blood flow and LV function were not significant. We did not observe net lactate production in any of the groups. Coronary blood flow increased out of proportion to Mvo₂ in group I animals. :We conclude that although L-NAME at 30 mg/kg causes vasoconstriction, its effects on coronary blood flow and LV function were not significant.