Antoine Kimmoun

Hemodynamic consequences of severe lactic acidosis in shock states: from bench to bedside

Lactic acidosis is a very common biological issue for shock patients. Experimental data clearly demonstrate that metabolic acidosis, including lactic acidosis, participates in the reduction of cardiac contractility and in the vascular hyporesponsiveness to vasopressors through various mechanisms. However, the contributions of each mechanism responsible for these deleterious effects have not been fully determined and their respective consequences on organ failure are still poorly defined, particularly in humans. Despite some convincing experimental data, no clinical trial has established the level at which pH becomes deleterious for hemodynamics. Consequently, the essential treatment for lactic acidosis in shock patients is to correct the cause. It is unknown, however, whether symptomatic pH correction is beneficial in shock patients. The latest Surviving Sepsis Campaign guidelines recommend against the use of buffer therapy with pH ≥7.15 and issue no recommendation for pH levels <7.15. Furthermore, based on strong experimental and clinical evidence, sodium bicarbonate infusion alone is not recommended for restoring pH. Indeed, bicarbonate induces carbon dioxide generation and hypocalcemia, both cardiovascular depressant factors. This review addresses the principal hemodynamic consequences of shock-associated lactic acidosis. Despite the lack of formal evidence, this review also highlights the various adapted supportive therapy options that could be putatively added to causal treatment in attempting to reverse the hemodynamic consequences of shock-associated lactic acidosis.

β1-Adrenergic Inhibition Improves Cardiac and Vascular Function in Experimental Septic Shock.

Objective:Preliminary experimental data suggest that selective &bgr;1-blockers may improve ex vivo cardiac function in animal sepsis. Currently, the effects of esmolol on in vivo cardiac function and on vascular function are unknown. The present study was designed to examine the effects of the &bgr;1-selective blocker esmolol on myocardial and vascular function in peritonitis-induced septic rats and to explore the inflammatory pathways involved in this process. Design:Randomized animal study. Setting:University research laboratory. Subjects:Male Wistar rats. Interventions:Four hours after cecal ligation and puncture, Wistar rats were randomly allocated to the following groups: control, esmolol, norepinephrine (started at 18 hr after the surgery), and esmolol (started at 4 hr after the surgery) + norepinephrine (started at 18 hr after the surgery). Assessment at 18 hours after surgery was focused on cardiac contractility and vascular ex vivo function. Cardiac and vascular protein expressions of nuclear factor &kgr;B and endothelial nitric oxide synthase/Akt/inducible nitric oxide synthase pathways were assessed by Western blotting. Measurements and Main Results:When compared with sham-operated animals, cecal ligation and puncture animals developed hypotension, cardiac depression, and vascular hyporesponsiveness to vasopressor treatment. Esmolol infusion increased cardiac contractility and restored mesenteric vasoreactivity. This effect was associated with a decrease in nuclear factor &kgr;B activation, an increase in Akt and endothelial nitric oxide synthase phosphorylation, and a decrease in inducible nitric oxide synthase expression both at the cardiac and vessel level. Esmolol infusion was also associated with an up-regulation in &agr;1-vascular adrenoreceptors. Conclusion:Adjunction of selective &bgr;1-blockade to standard septic shock management enhances intrinsic cardiac contractility and vascular responsiveness to catecholamines. These protective cardiovascular effects are likely predominantly attributed to the anti-inflammatory effect of esmolol.

Efficient extra- and intracellular alkalinization improves cardiovascular functions in severe lactic acidosis induced by hemorrhagic shock.

Background:Lactic acidosis is associated with cardiovascular failure. Buffering with sodium bicarbonate is proposed in severe lactic acidosis. Bicarbonate induces carbon dioxide generation and hypocalcemia, both cardiovascular depressant factors. The authors thus investigated the cardiovascular and metabolic effects of an adapted sodium bicarbonate therapy, including prevention of carbon dioxide increase with hyperventilation and ionized calcium decrease with calcium administration. Methods:Lactic acidosis was induced by hemorrhagic shock. Twenty animals were randomized into five groups: (1) standard resuscitation with blood retransfusion and norepinephrine (2) adapted sodium bicarbonate therapy (3) nonadapted sodium bicarbonate therapy (4) standard resuscitation plus calcium administration (5) hyperventilation. Evaluation was focused in vivo on extracellular pH, on intracellular pH estimated by P31 nuclear magnetic resonance and on myocardial contractility by conductance catheter. Aortic rings and mesenteric arteries were isolated and mounted in a myograph, after which arterial contractility was measured. Results:All animals in the hyperventilation group died prematurely and were not included in the statistical analysis. When compared with sham rats, shock induced extracellular (median, 7.13; interquartile range, [0.10] vs. 7.30 [0.01]; P = 0.0007) and intracellular acidosis (7.26 [0.18] vs. 7.05 [0.13]; P = 0.0001), hyperlactatemia (7.30 [0.01] vs. 7.13 [0.10]; P = 0.0008), depressed myocardial elastance (2.87 [1.31] vs. 0.5 [0.53] mmHg/&mgr;l; P = 0.0001), and vascular hyporesponsiveness to vasoconstrictors. Compared with nonadapted therapy, adapted bicarbonate therapy normalized extracellular pH (7.03 [0.12] vs. 7.36 [0.04]; P < 0.05), increased intracellular pH to supraphysiological values, improved myocardial elastance (1.68 [0.41] vs. 0.72 [0.44] mmHg/&mgr;l; P < 0.05), and improved aortic and mesenteric vasoreactivity. Conclusions:A therapeutic strategy based on alkalinization with sodium bicarbonate along with hyperventilation and calcium administration increases pH and improves cardiovascular function.

Fatal cardiac arrhythmia following voluntary caffeine overdose in an amateur body-builder athlete☆

Caffeine (1,3,7-trimethylxanthine, CAS 58-08-2) is one of the most commonly consumed substances in the world and is well known to have extensive effects on physiological functions, especially on the cardiovascular system. We report a fatal cardiac arrhythmia following voluntary caffeine overdose in an amateur body-builder athlete.

Mechanisms of Vascular Hyporesponsiveness in Septic Shock

PURPOSE To define some of the most common characteristics of vascular hyporesponsiveness to catecholamines during septic shock and outline current therapeutic approaches and future perspectives. METHODS Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. RESULTS NO and peroxynitrite are mainly responsible for vasoplegia and vascular hyporeactivity while COX 2 enzyme is responsible for the increase in PGI2, which also contributes to hyporeactivity. Moreover, K+ATP and BKCa channels are over-activated during septic shock and participate in hypotension. Finally, other mechanisms are involved in vascular hyporesponsiveness such as critical illness-related corticosteroid insufficiency, vasopressin depletion, dysfunction and desensitization of adrenoreceptors as well as inactivation of catecholamines by oxidation. CONCLUSION In animal models, several therapeutic approaches, targeted on one particular compound have proven their efficacy in preventing or reversing vascular hyporesponsiveness to catecholamines. Unfortunately, none have been successfully tested in clinical trials. Nevertheless, very high doses of catecholamines ( > 5 μg/kg/min), hydrocortisone, terlipressin or vasopressin could represent an alternative for the treatment of refractory septic shock.

Prone positioning use to hasten veno-venous ECMO weaning in ARDS

Dear Editor, A 41-year-old overweight (body mass index 35 kg/m) woman was admitted from home to the intensive care unit (ICU) for acute respiratory distress with fever. Her medical history mainly included a neurosarcoidosis treated with corticosteroids, methotrexate and six courses of cyclophosphamide. The computed tomography scan revealed a diffuse alveolar–interstitial syndrome without any mediastinal adenopathy. She received an initial antibiotherapy (cephalosporine, rovamycin) after an examination for infectious diseases. No infectious process or cause for an acute exacerbation of pulmonary sarcoidosis was found in the bronchoalveolar lavage fluid, and antibiotherapy was stopped after 5 days. There was no acute cardiac dysfunction on echocardiography. No diagnosis was made and her respiratory state worsened. She required, after 6 days of evolution, invasive mechanical ventilation to treat an acute respiratory distress syndrome (ARDS). After 3 days of lung protective ventilation [normal tidal volume (Vt) 5 ml/kg, respiratory rate (RR) 30/min, positive end expiratory pressure (PEEP) 12 cmH2O, plateau pressure (PP) 30 cmH2O, static compliance (SC) 20 ml/cmH2O) with neuromuscular blockade, she remained with a severe ARDS [partial pressure of oxygen in the blood (PaO2)/fraction of inspired oxygen (FiO2) 85 mmHg]. Two 24-h sessions of prone positioning failed to improve the PaO2/FiO2. No evolutive infectious process was found, and corticosteroids were maintained at 1 mg/kg/day to treat the ARDS inflammatory process. Her respiratory function worsened (Vt 5 ml/kg, RR 35/min, PEEP 10 cmH2O, PP 30 cmH2O, SC 20 ml/cmH2O) with refractory hypoxia on arterial gasometry [FiO2 100 %, pH 7.45; partial pressure oxygen (PO2) 75 mmHg; PCO2 40 mmHg; HCO3 -

Compared effects of inhibition and exogenous administration of hydrogen sulphide in ischaemia-reperfusion injury

IntroductionHaemorrhagic shock is associated with an inflammatory response consecutive to ischaemia-reperfusion (I/R) that leads to cardiovascular failure and organ injury. The role of and the timing of administration of hydrogen sulphide (H2S) remain uncertain. Vascular effects of H2S are mainly mediated through K+ATP-channel activation. Herein, we compared the effects of D,L-propargylglycine (PAG), an inhibitor of H2S production, as well as sodium hydrosulphide (NaHS), an H2S donor, on haemodynamics, vascular reactivity and cellular pathways in a rat model of I/R. We also compared the haemodynamic effects of NaHS administered before and 10 minutes after reperfusion.MethodsMechanically ventilated and instrumented rats were bled during 60 minutes in order to maintain mean arterial pressure at 40 ± 2 mmHg. Ten minutes prior to retransfusion, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl) or PAG (50 mg/kg). PNU, a pore-forming receptor inhibitor of K+ATP channels, was used to assess the role of K+ATP channels.ResultsShock and I/R induced a decrease in mean arterial pressure, lactic acidosis and ex vivo vascular hyporeactivity, which were attenuated by NaHS administered before reperfusion and PNU but not by PAG and NaHS administered 10 minutes after reperfusion. NaHS also prevented aortic inducible nitric oxide synthase expression and nitric oxide production while increasing Akt and endothelial nitric oxide synthase phosphorylation. NaHS reduced JNK activity and p-P38/P38 activation, suggesting a decrease in endothelial cell activation without variation in ERK phosphorylation. PNU + NaHS increased mean arterial pressure when compared with NaHS or PNU alone, suggesting a dual effect of NaHS on vascular reactivity.ConclusionNaHS when given before reperfusion protects against the effects of haemorrhage-induced I/R by acting primarily through a decrease in both proinflammatory cytokines and inducible nitric oxide synthase expression and an upregulation of the Akt/endothelial nitric oxide synthase pathway.Keywords: hydrogen sulphide, inflammation mediators, therapeutic use, shock, hemorrhagic/drug therapy, haemodynamics/drug effects

Evaluation of Cardiac Function Index as Measured by Transpulmonary Thermodilution as an Indicator of Left Ventricular Ejection Fraction in Cardiogenic Shock

Introduction. The PiCCO transpulmonary thermodilution technique provides two indices of cardiac systolic function, the cardiac function index (CFI) and the global ejection fraction (GEF). Both appear to be correlated with left ventricular ejection fraction (LVEF) measured by echocardiography in patients with circulatory failure, especially in septic shock. The aim of the present study was to test the reliability of CFI as an indicator of LVEF in patients with cardiogenic shock. Methods. In thirty-five patients with cardiogenic shock, we performed (i) simultaneous measurements of echocardiography LVEF and cardiac function index assessed by transpulmonary thermodilution (n = 72) and (ii) transpulmonary thermodilution before/after increasing inotropic agents (n = 18). Results. Mean LVEF was 31% (+/−11.7), CFI 3/min (+/−1), and GEF 14.2% (+/−6). CFI and GEF were both positively correlated with LVEF (P < 0.0001, r 2 = 0.27). CFI and GEF were significantly increased with inotropic infusion (resp., P = 0.005, P = 0.007). A cardiac function index <3.47/min predicted a left ventricular ejection fraction ≤35% (sensitivity 81.1% and specificity 63%). In patients with right ventricular dysfunction, CFI was not correlated with LVEF. Conclusion. CFI is correlated with LVEF provided that patient does not present severe right ventricular dysfunction. Thus, the PiCCO transpulmonary thermodilution technique is useful for the monitoring of inotropic therapy during cardiogenic shock.

Shock state: an unrecognized and underestimated presentation of drug reaction with eosinophilia and systemic symptoms.

ABSTRACT Some patients with drug reaction with eosinophilia and systemic symptoms (DRESS) are probably admitted in intensive care unit (ICU), but data concerning their clinical features at admission are scarce. Therefore, in the present study, we used a clinical network of French intensivists to study the clinical features and evolution of DRESS patients hospitalized in ICU. A national, retrospective, multicenter study collected DRESS cases hospitalized in ICU for DRESS from 2000 to end of 2011. All files were analyzed through the RegiSCAR scoring system as “no,” “possible,” “probable,” or “definite” DRESS. Patients were included only if they had a probable or definite DRESS. Demographic, hemodynamic, biological, and infectious data were recorded. Twenty-one patients were included. Hospital mortality was 10 (47%) of 21, and 16 of 21 patients had on admission a shock state necessitating vasopressor agents. Echocardiographic ejection fraction in shock patients was depressed (47% ± 13%). Mechanical ventilation was required in 13 of 21 cases. Hepatic failure was observed in 11 of 21 cases, acute renal failure in 18 of 20 cases, and lactic acidosis in 12 of 20 patients. Initial bacteriology was negative in all patients. Human herpesvirus reactivations were found in five of 15 cases. In conclusion, shock without bacteriological documentation associated with multiple organ failure is the most common presentation of DRESS at admission in ICU and is associated with a higher mortality than previously described.

Improving blood oxygenation during venovenous ECMO for ARDS

Dear Editor, Schmidt et al. [1] elegantly demonstrated that pump blood flow is a major determinant of oxygenation in patients treated with venovenous ECMO for ARDS. In this report, the authors proposed certain tools to improve oxygenation in such patients. Their proposals were mainly based on optimization of tissue oxygen delivery using large cannula size and transfusion. Based on the fact that an ECMO flow/cardiac output ratio of greater than 60 is constantly associated with adequate blood oxygenation and oxygen transport and delivery, we propose another means to improve oxygenation in patients treated with VV ECMO with inadequate oxygenation due to an imbalance between ECMO blood flow/cardiac output. The first is the use of moderate hypothermia which is very easy to obtain in such patients since blood temperature is controlled during ECMO. Table 1 represents the evolution of oxygen saturation in a patient treated with ECMO for ARDS secondary to H1N1 influenza complicated by severe septic shock requiring very high norepinephrine doses. The patient was severely vasoplegic with a subsequent highly elevated cardiac output. Decreasing body temperature from 37 C to 34 C markedly improved oxygen saturation. Meanwhile, as suggested by Schortgen et al. [2] norepinephrine doses were reduced. In this case, oxygen saturation improvement is likely due to both an increase in ECMO flow/cardiac output due to cardiac output decrease and a decrease in pulmonary shunt secondary to high blood flow. The second approach to improve ECMO flow/cardiac output is to reduce cardiac output using esmolol, a short-acting selective beta-1 blocking agent. The reduction in cardiac output is parallel to the decrease in heart rate. Table 2 represents the theoretical evolution of ECMO flow/ cardiac output in using esmolol to reduce heart rate. We hypothesize that stroke volume remains constant during esmolol infusion and that the reduction in cardiac output does not interfere with venous return. These two hypotheses require clinical confirmation however. The use of esmolol could be considered even in patients treated with norepinephrine as recently demonstrated [3]. To conclude, in some patients treated with VV-ECMO and high cardiac output, oxygen saturation could be improved by increasing pump blood flow as high as possible and in reducing cardiac output through the use of moderate hypothermia and/or esmolol.