Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.

In acquired thrombotic thrombocytopenic purpura (TTP), the persistence of severe ADAMTS13 deficiency (<10%) during remission is associated with more relapse. Preemptive (ie, after remission) administration of rituximab in these patients to prevent relapses remains controversial. We performed a cross-sectional analysis of 12-year follow-up data to compare the relapse incidence with or without preemptive rituximab infusion. Among 48 patients who experienced at least one episode of acquired TTP followed by severe ADAMTS13 deficiency during remission, 30 received preemptive rituximab (group 1); the other 18 did not (group 2). After a median of 17 months (interquartile range [IQR], 11-29) following rituximab, the relapse incidence decreased from 0.57 episodes/year (IQR, 0.46-0.7) to 0 episodes/year (IQR, 0-0.81) (P < .01) in group 1. ADAMTS13 activity 3 months after the first rituximab infusion increased to 46% (IQR, 30%-68%). Nine patients required additional courses of rituximab. In 5 patients, ADAMTS13 activity failed to increase durably. Four patients experienced manageable adverse effects. In group 2, the relapse incidence was higher (0.5 relapses/year; IQR, 0.12-0.5; P < .01). Relapse-free survival was longer in group 1 (P = .049). A persistent severe ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses.

High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP. STUDY DESIGN AND METHODS: We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded. RESULTS: Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor (TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174A-2848G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP. CONCLUSION: Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP.

Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura is still associated with a 10-20% death rate. It has still not been possible to clearly identify early prognostic factors of death. This study involved thrombotic thrombocytopenic purpura patients with acquired severe (<10% of normal activity) ADAMTS13 deficiency and aimed to identify prognostic factors associated with 30-day death. DESIGN AND METHODS: The study involved a prospective cohort of patients and was carried out between October 2000 and August 2010. A validation cohort of patients was set up from September 2010 to August 2011. Altogether, 281 (analysis cohort) and 66 (validation cohort) consecutive adult thrombotic thrombocytopenic purpura patients with acquired severe ADAMTS13 deficiency were enrolled. The study evaluated 30-day mortality after treatment initiation according to characteristics at inclusion. RESULTS: Non-survivors (11%) were older (P=10(-6)) and more frequently presented arterial hypertension (P=5.10(-4)) and ischemic heart disease (P=0.013). Prognosis was increasingly poor with age (P=0.004). On presentation, cerebral manifestations were more frequent in non-survivors (P=0.018) and serum creatinine level was higher (P=0.008). The most significant independent variables determining death were age, severe cerebral involvement and LDH level 10 N or over. A 3-level risk score for early death was defined and confirmed in the validation cohort using these variables, with higher values corresponding to increased risk of early death. CONCLUSIONS: A risk score for early death was defined in patients with thrombotic thrombocytopenic purpura and validated on an independent cohort. This score should help to stratify early treatment and identify patients with a worse prognosis.

Noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial.

RATIONALE: The use of noninvasive ventilation (NIV) as an early weaning/extubation technique from mechanical ventilation remains controversial. OBJECTIVES: To investigate NIV effectiveness as an early weaning/extubation technique in difficult-to-wean patients with chronic hypercapnic respiratory failure (CHRF). METHODS: In 13 intensive care units, 208 patients with CHRF intubated for acute respiratory failure (ARF) who failed a first spontaneous breathing trial were randomly assigned to three groups: conventional invasive weaning group (n = 69), extubation followed by standard oxygen therapy (n = 70), or NIV (n = 69). NIV was permitted as rescue therapy for both non-NIV groups if postextubation ARF occurred. Primary endpoint was reintubation within 7 days after extubation. Secondary endpoints were: occurrence of postextubation ARF or death within 7 days after extubation, use of rescue postextubation NIV, weaning time, and patient outcomes. MEASUREMENTS AND MAIN RESULTS: Reintubation rates were 30, 37, and 32% for invasive weaning, oxygen-therapy, and NIV groups, respectively (P = 0.654). Weaning failure rates, including postextubation ARF, were 54, 71, and 33%, respectively (P < 0.001). Rescue NIV success rates for invasive and oxygen-therapy groups were 45 and 58%, respectively (P = 0.386). By design, intubation duration was 1.5 days longer for the invasive group than in the two others. Apart from a longer weaning time in NIV than in invasive group (2.5 vs. 1.5 d; P = 0.033), no significant outcome difference was observed between groups. CONCLUSIONS: No difference was found in the reintubation rate between the three weaning strategies. NIV decreases the intubation duration and may improve the weaning results in difficult-to-wean patients with CHRF by reducing the risk of postextubation ARF. The benefit of rescue NIV in these patients deserves confirmation.

Interface strategy during noninvasive positive pressure ventilation for hypercapnic acute respiratory failure.

OBJECTIVE: To assess the influence of initial mask choice on the clinical effectiveness and tolerance of noninvasive positive pressure ventilation (NIPPV) in the management of hypercapnic acute respiratory failure. DESIGN: A prospective randomized controlled clinical study. SETTING: A medical intensive care unit at a university hospital. INTERVENTION: Randomization between two NIPPV interfaces. PATIENTS: Initial mask choice was randomized between two standard masks: face (NIPPVf group) and nasal (NIPPVn group). The main end point was mask failure (i.e., mask change and/or intubation). Secondary end points were tolerance of NIPPV, change in respiratory parameters during the first 3 days, and patient outcome. Results were analyzed on an intent to treat basis. A per protocol analysis was also conducted. MAIN RESULTS: Ninety patients with underlying chronic lung disease were included, 46 in the NIPPVf group and 44 in the NIPPVn group. The overall success rate of NIPPV was 83%. Mask failure occurred significantly more often in the NIPPVn group (32/44 vs. 9/46; p < 0.0001), mainly because of the need for mask change (32/44 vs. 0/46; p < 0.0001) because of the occurrence of major buccal air-leaks in 94% of cases. Improvement in respiratory parameters was similar in the two groups. Whereas air-leaks were more frequent in the NIPPVn group (p < 0.05), respiratory comfort was assessed as lower and complications more frequent by the staff in the NIPPVf group from day 2 (p < 0.05). CONCLUSIONS: A face mask should be the first-line strategy in the initial management of hypercapnic acute respiratory failure with NIPPV. However, if NIPPV has to be prolonged, switching to a nasal mask may improve comfort by reducing face mask complications.

Detection of Neisseria meningitidis DNA from skin lesion biopsy using real-time PCR: usefulness in the aetiological diagnosis of purpura fulminans.

OBJECTIVE: The present study evaluated the usefulness of a real-time polymerase chain reaction (rtPCR) assay for the detection of Neisseria meningitidis (Nm) and genogrouping on skin lesion biopsies in patients with purpura fulminans (PF). DESIGN: Retrospective single-centre study. SETTING: Adult and paediatric intensive care units at the University Hospital of Rouen. PATIENTS: All patients admitted between January 2000 and January 2006, with a final diagnosis of PF and for which a skin biopsy and blood cultures were performed, were included. INTERVENTIONS: Skin biopsy and blood cultures were used for culture and rtPCR. MEASUREMENTS AND MAIN RESULTS: Thirty-four patients fulfilled the criteria (27 children and 7 adults). Nm rtPCR performed on skin biopsy was positive in 100% (34/34) of cases, compared with only 14.7% (5/34) for skin culture (p=0.0001). rtPCR genogrouping on skin biopsy was positive in 58.8% (20/34) of the cases compared with 14.7% (5/34) for skin culture (p=0.0013). For patients (n=17) in whom rtPCR was performed both on blood and skin biopsy, skin biopsy gave a significantly higher rate of Nm detection [100% (17/17) vs. 58.8% (10/17); p=0.023] and genogroup characterisation [76.5% (13/17) vs. 35.3% (6/17); p=0.045] than blood. We encountered no specimen with culture-positive and rtPCR-negative results (negative predictive value of rtPCR 100%). CONCLUSION: In suspected PF cases, skin biopsy is more reliable to identify Nm and its genogroup than blood or, probably, CSF, especially when PCR methods are used. This could help the implementation of public health interventions, especially concerning a vaccination policy.

Diaphragmatic effects of selective resection of the upper phrenic nerve root in dogs.

The aim of this study was to evaluate the effects on the diaphragm of upper phrenic nerve root resections in dogs. During laryngeal reinnervation, selective resections of the upper phrenic nerve root (C5) were performed unilaterally (right side, n=7; Group A) and bilaterally (n=6; Group B) and compared to non denervated animals (n=5). After 8 months, a diaphragmatic evaluation was performed: X-ray, EMG, transdiaphragmatic pressure (Pdi) after ipsi- and bilateral tetanic stimulation of the phrenic nerves and a bilateral histological study of five hemidiaphragmatic regions. EMG alterations were significantly more severe in Group B than in Group A, for the left (p<0.05) and right hemidiaphragms (p<0.01). No differences in the X-rays were noted between the three groups. The Pdi of the three groups after occlusion and phrenic nerve stimulations (unilateral and bilateral) were not statistically different. Histological data demonstrated that there were no differences in fibre irregularity, predominant fibre type or fibrosis between the three groups. Macroscopic and microscopic atrophy, which was mainly present on the anterior regions of the hemidiaphragms, was significantly higher in Group B than in Group A and undenervated dogs (p<0.05). In conclusion, resection of the upper phrenic nerve root of one phrenic nerve (right side) have limited effect on the diaphragm in dogs. However, resection of the upper phrenic nerve root on both sides resulted in a significant effect on the EMGs and histology of the entire diaphragm without any significant consequences on transdiaphragmatic pressure.

Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis.

OBJECTIVE: To report on the development and treatment of thrombotic microangiopathy, an atypical cause of acute renal failure in patients with acute pancreatitis. DESIGN: Case reports. SETTING: A 21-bed medical intensive care unit at an university hospital. PATIENTS: Two men with acute pancreatitis presented with acute renal failure, neurological manifestations, haemolytic anaemia and thrombocytopenia. Both patients required intensive care. MEASUREMENTS: Fragmented red cell count; levels of haptoglobin, amylase and lipase; serological testing for Escherichia Coli O157; computed tomography of the abdomen. MAIN RESULTS: The patients' courses were rapidly favourable after daily plasma exchange. A review of the existing medical literature was also undertaken. CONCLUSION: As thrombotic microangiopathy may be life-threatening without administration of fresh frozen plasma or plasma exchange, physicians should consider this disease as a possible cause of acute renal failure in patients with acute pancreatitis.

Gastric emptying in mechanically ventilated critically ill patients: effect of neuromuscular blocking agent.

OBJECTIVE: To assess gastrointestinal function in critically ill patients receiving muscle relaxant and to test clinical tolerance to enteral nutrition. DESIGN AND SETTING: Prospective study in an intensive care unit. PATIENTS: 20 critically ill patients requiring sedation with muscle relaxant to obtain adequate mechanical ventilation. MEASUREMENTS AND RESULTS: Patients were randomly selected to receive infusions of opioid sedation during the first session (session 1) and the same sedation with muscle relaxation (cisatracurium) during the second session (session 2). Gastric emptying was assessed by the paracetamol absorption technique. Following the paracetamol absorption 200 ml enteral feed was given, and the residual gastric volume was measured 1 and 2 h after feeding. The maximum plasma concentration (Cmax) was 14 mg/l (range 5-26) when patients received sedation, and 12 mg/l (range 5-30) when they received muscle relaxant. The target time for reaching the maximum plasma concentration (Tmax) was 30 min (range 20-60) and 35 min (range 20-60), respectively, in sessions 1 and 2. There was no significant difference between the two session as regards Tmax, Cmax, or AUC(0-120). The residual volumes were 110+/-65 ml (H1) and 95+/-76 ml (H2) during session 1 and 125+/-85 ml (H1) and 105+/-90 ml (H2) during session 2. CONCLUSIONS: Enteral feeding is one of the most effective methods of supporting nutritional needs in the critically ill patient. We conclude that in critically ill patients requiring sedation gastric emptying is not improved by neuromuscular blocking agent.

Influence of respiratory rate on gas trapping during low volume ventilation of patients with acute lung injury.

OBJECTIVE: Reduction in tidal volume (Vt) associated with increase in respiratory rate to limit hypercapnia is now proposed in patients with acute lung injury (ALI). The aim of this study was to test whether a high respiratory rate induces significant intrinsic positive end-expiratory pressure (PEEPi) in these patients. DESIGN: Prospective crossover study. SETTING: A medical intensive care unit. INTERVENTIONS AND MEASUREMENTS: Ten consecutive patients fulfilling criteria for severe ALI were ventilated with a 6 ml/kg Vt, a total PEEP level at 13+/-3 cmH(2)O and a plateau pressure kept at 23+/-4 cmH(2)O. The respiratory rate was randomly set below 20 breaths/min (17+/-3 breaths/min) and increased to 30 breaths/min (30+/-3 breaths/min) to compensate for hypercapnia. External PEEP was adjusted to keep the total PEEP and the plateau pressure constant. PEEPi was computed as the difference between total PEEP and external PEEP. The lung volume retained by PEEPi was then measured. RESULTS: Increase in respiratory rate resulted in significantly higher PEEPi (1.3+/-0.4 versus 3.9+/-1.1 cmH(2)O, p<0.01) and trapped volume (70+/-43 versus 244+/-127 ml, p<0.01). External PEEP needed to be reduced from 11.9+/-3.4 to 9.7+/-2.9 cmH(2)O ( p<0.01). PaO(2) was not affected but the alveolar-arterial oxygen tension difference slightly worsened with the high respiratory rate (p<0.05). CONCLUSIONS: An increase in respiratory rate used to avoid Vt reduction-induced hypercapnia may induce substantial gas trapping and PEEPi in patients with ALI.

Erythropoietin and renin as biological markers in critically ill patients.

INTRODUCTION: During sepsis the endocrine, immune and nervous systems elaborate a multitude of biological responses. Little is known regarding the mechanisms responsible for the final circulating erythropoietin (EPO) and renin levels in septic shock. The aim of the present study was to assess the role of EPO and renin as biological markers in patients with septic shock. METHODS: A total of 44 critically ill patients with septic shock were evaluated. RESULTS: Nonsurvivors had significantly higher serum EPO levels than did survivors on admission (median [minimum-maximum]; 61 [10-602] versus 20 [5-369]). A negative relationship between serum EPO and blood haemoglobin concentrations was observed in the survivor group (r = -0.61; P < 0.001). In contrast, in the nonsurvivors the serum EPO concentration was independent of the blood haemoglobin concentration. Furthermore, we observed significant relationships between EPO concentration and lactate (r = 0.5; P < 0.001), arterial oxygen tension/fractional inspired oxygen ratio (r = -0.41; P < 0.005), arterial pH (r = -0.58; P < 0.001) and renin concentration (r = 0.42; P < 0.005). With regard to renin concentration, significant correlations with lactate (r = 0.52; P < 0.001) and arterial pH (r = -0.33; P < 0.05) were observed. CONCLUSION: Our findings show that EPO and renin concentrations increased in patients admitted to the intensive care unit with septic shock. Renin may be a significant mediator of EPO upregulation in patients with septic shock. Further studies regarding the regulation of EPO expression are clearly warranted.

Boussignac continuous positive airway pressure device in the emergency care of acute cardiogenic pulmonary oedema: a randomized pilot study.

This study aimed to assess the short-term respiratory effects of a new portable device that delivers a continuous positive airway pressure via a face mask (Boussignac-CPAP) in patients with severe acute cardiogenic pulmonary oedema, and the feasibility of using this technique in an emergency department. We prospectively studied 30 consecutive patients with acute cardiogenic pulmonary oedema. They were randomly assigned either to the Boussignac-CPAP valve, which delivered oxygen, or to standard oxygen delivery for a duration of 30 min. The end-expiratory pressure reached 9.3+/-0.3 cm H2O with the Boussignac-CPAP valve. At the end of the 30 min period, the decreases in respiratory rate and muscular activity were significantly greater among patients assigned to the Boussignac-CPAP valve compared with those on standard oxygen delivery [24+/-1.6 breaths/min, median 24 (15-37) versus 28.5+/-1.9, median 27 (16-38) and 1.3+/-0.2, median 1 (0-4) versus 2.7+/-0.3, median 2 (0-4), respectively]. Moreover, the arterial oxygen tension to inspired oxygen concentration ratio and tidal volume were improved at the end of the 30 min Boussignac-CPAP period compared with baseline. Boussignac-CPAP was easily implemented and no side-effects were reported. Continuous positive pressure delivered using the Boussignac-CPAP device is feasible in an emergency care setting. It can quickly improve respiratory distress in acute cardiogenic pulmonary oedema patients. A larger trial should be initiated in such an emergency care setting to demonstrate the effectiveness of the Boussignac-CPAP device.

Noninvasive mechanical ventilation in clinical practice: a 2-year experience in a medical intensive care unit.

OBJECTIVE: To evaluate the feasibility and outcome results of noninvasive mechanical ventilation (NIV) in daily clinical practice outside any prospective protocol-driven trial. DESIGN: An observational retrospective cohort study. SETTING: A 22-bed medical intensive care unit in a university hospital. PATIENTS: A consecutive cohort of 124 patients who underwent 143 NIV trials, regardless of the indication, over two consecutive years (1997-1998). INTERVENTIONS: None. RESULTS: A total of 604 acute respiratory failure patients underwent mechanical ventilation, and 143 NIVs were performed in 124 patients. The overall prevalence of NIV use was 143 of 604 patients (24%) in three groups: hypoxemic acute respiratory failure (29.5%), hypercapnic acute respiratory failure (41%), and weaning/postextubation (29.5%). Intubation was avoided in 92 of 143 of the NIVs performed (64%), 19 (13%) after changing the initial NIV mode (i.e., a success rate of 62%, 51%, and 86% in the three groups, respectively). A total of 35 of 51 intubated patients (69%) required intubation during the first 24 hrs of NIV. Intensive care unit stay was 12 +/- 10 days for the overall population, and mortality, when NIV failed, was 13 of 124 patients (10.5%). Arterial pH (p =.0527) and the Pao2/Fio2 ratio (p =.0482) after 1 hr were the only independent predictive factors for NIV failure by multivariate analysis. CONCLUSIONS: This study confirms the results of controlled trials and demonstrates the feasibility and efficacy of NIV applied in daily clinical practice. These results suggest that NIV should be considered as a first-line ventilatory treatment in various etiologies of acute respiratory failure and as a promising weaning technique and postextubation ventilatory support. However, NIV should certainly be performed by a motivated and sufficiently trained care team.

Mechanical effects of airway humidification devices in difficult to wean patients.

OBJECTIVE: To evaluate the influence of airway humidification devices on the efficacy of ventilation in difficult to wean patients. DESIGN: A prospective, randomized, controlled physiologic study. SETTING: A 22-bed medical intensive care unit in a university hospital. PATIENTS: Chronic respiratory failure patients. INTERVENTIONS: Performances of a heated humidifier and a heat and moisture exchanger were evaluated on diaphragmatic muscle activity, breathing pattern, gas exchange, and respiratory comfort during weaning from mechanical ventilation by using pressure support ventilation. Eleven patients with chronic respiratory failure were submitted to four pressure support ventilation sequences by using the heated humidifier and the heat and moisture exchanger at two different levels of pressure support ventilation (7 and 15 cm H(2)O). MEASUREMENT AND MAIN RESULTS: Compared with the heated humidifier and regardless of the pressure support ventilation level used, the heat and moisture exchanger significantly increased all of the inspiratory effort variables (inspiratory work of breathing expressed in J/L and J/min, pressure time product, changes in esophageal pressure, and transdiaphragmatic pressure; p <.05) and dynamic intrinsic positive end-expiratory pressure (p <.05). Similarly, the heat and moisture exchanger produced a significant increase in Paco(2) (p <.01) responsible for severe respiratory acidosis (p <.05), which was insufficiently compensated for despite a significant increase in minute ventilation (p <.05). This resulted in respiratory discomfort for all patients with the heat and moisture exchanger (p <.01). Adverse effects were partially counterbalanced by increasing the pressure support ventilation level with the heat and moisture exchanger by >or=8 cm H(2)O. CONCLUSIONS: The type of airway humidification device used may negatively influence the mechanical efficacy of ventilation and, unless the pressure support ventilation level is considerably increased, the use of a heat and moisture exchanger should not be recommended in difficult or potentially difficult to wean patients with chronic respiratory failure.

Respective effects of end-expiratory and end-inspiratory pressures on alveolar recruitment in acute lung injury.

OBJECTIVE: A low tidal volume can induce alveolar derecruitment in patients with acute lung injury. This study was undertaken to evaluate whether this resulted mainly from the decrease in tidal volume or from the reduction in end-inspiratory plateau pressure and whether there is any benefit in raising the level of positive end-expiratory pressure (PEEP) while plateau pressure is kept constant. DESIGN: Prospective crossover study. SETTING: Medical intensive care unit of a university teaching hospital. PATIENTS: Fifteen adult patients ventilated for acute lung injury (PaO2/FiO2, 158 +/- 34 mm Hg; lung injury score, 2.7 +/- 0.6). INTERVENTIONS: Three combinations were tested: PEEP at the lower inflection point with 6 mL/kg tidal volume, PEEP at the lower inflection point with 10 mL/kg tidal volume, and high PEEP with tidal volume at 6 mL/kg, keeping the plateau pressure similar to the preceding condition. MEASUREMENTS AND MAIN RESULTS: Pressure-volume curves at zero PEEP and at set PEEP were recorded, and recruitment was calculated as the volume difference between both curves for pressures ranging from 15 to 30 cm H2O. Arterial blood gases were measured for all patients. For a similar PEEP at the lower inflection point (10 +/- 3 cm H2O), tidal volume reduction (10 to 6 mL/kg) led to a significant derecruitment. A low tidal volume (6 mL/kg) with high PEEP (14 +/- 3 cm H2O), however, induced a significantly greater recruitment and a higher Pao than the two other strategies. CONCLUSION: At a given plateau pressure (i.e., similar end-inspiratory distension), lowering tidal volume and increasing PEEP increase recruitment and PaO2.

Gastric mucosal acidosis and cytokine release in patients with septic shock.

OBJECTIVE: It has been postulated that in critically ill patients, splanchnic hypoperfusion may lead to cytokine release into the systemic circulation. The presence of cytokines could trigger an inflammatory response and cause multiple organ dysfunction syndrome. Although experimental studies support this hypothesis, humans studies remain controversial. The aim of the study was to determine the relationship between splanchnic hypoperfusion and cytokine release during septic shock. DESIGN: Human prospective study. SETTING: Medical intensive care unit at a university hospital. PATIENTS: A total of 30 patients with mean arterial pressure of <60 mm Hg after volume loading with either oliguria or hyperlactatemia. MEASUREMENTS: Gastric intramucosal measurements as an indicator of splanchnic hypoperfusion and blood samples were obtained at admission to the medical intensive care unit and repeated during 48 hrs. Cytokine (tumor necrosis factor-alpha and interleukin-6) values were evaluated by enzyme-linked immunoassays at the following periods: at the time of admission and 2, 4, 8, 12, 24, 36, and 48 hrs later. MAIN RESULTS: High levels of interleukin-6 and tumor necrosis factor-alpha were observed at admission in survivors and nonsurvivors, without significant difference. At 48 hrs, cytokine levels were significantly higher in patients who died compared with the survivors (tumor necrosis factor: 163 +/- 16 for nonsurvivors vs. 34 +/- 9 ng/mL for survivors; interleukin-6: 2814 +/- 485 for nonsurvivors vs. 469 +/- 107 ng/mL for survivors). At 48 hrs, the PCO2 gap was significantly higher in the nonsurvivors compared with survivors (25.87 +/- 2.73 vs. 11.35 +/- 2.25 mm Hg), despite systemic hemodynamic variables in the normal range. A positive relationship was demonstrated between plasma levels of tumor necrosis factor-alpha and interleukin-6 and the PCO2 gap throughout the study. The PCO2 gap was not correlated with hemodynamic variables. CONCLUSIONS: Our data suggest a relationship between gastric mucosal acidosis, as assessed by PCO2 gap, and cytokine levels in critically ill patients with septic shock. Gut injury may be a contributor of the inflammatory response in patients with septic shock.