Anders Larsson

Sepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality. Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its’ anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis. To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n=8) or control (saline, n=8) group. After onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), resuscitation was initiated by an infusion of AF-16 or saline. We recorded respiratory and hemodynamic parameters hourly for twenty hours and collected post mortem tissue samples at the end of the experiment. No differences between the groups were observed regarding hemodynamics, fluid balance, lung mechanics, gas exchange or histology. This experimental study suggests that AF-16 does not modulate sepsis symptoms in peritonitis induced sepsis.

Modern ventilatory strategies are based on the assumption that lung terminal airspaces act as isotropic balloons that progressively accommodate gas. Phase contrast synchrotron radiation computed tomography (PCSRCT) has recently challenged this concept, showing that in healthy lungs, deflation mechanisms are based on the sequential de-recruitment of airspaces. Using PCSRCT scans in an animal model of acute respiratory distress syndrome (ARDS), this study examined whether the numerosity (ASnum) and dimension (ASdim) of lung airspaces change during a deflation maneuver at decreasing levels of positive end-expiratory pressure (PEEP) at 12, 9, 6, 3, and 0 cmH₂O. Deflation was associated with significant reduction of ASdim both in the whole lung section (passing from from 13.1 ± 2.0 at PEEP 12 to 7.6 ± 4.2 voxels at PEEP 0) and in single concentric regions of interest (ROIs). However, the regression between applied PEEP and ASnum was significant in the whole slice (ranging from 188 ± 52 at PEEP 12 to 146.4 ± 96.7 at PEEP 0) but not in the single ROIs. This mechanism of deflation in which reduction of ASdim is predominant, differs from the one observed in healthy conditions, suggesting that the peculiar alveolar micromechanics of ARDS might play a role in the deflation process.

Veno-venous extracorporeal carbon dioxide (CO2) removal (vv-ECCO2R) is increasingly being used in the setting of acute respiratory failure. Blood flow rates range in clinical practice from 200 mL/min to more than 1500 mL/min, and sweep gas flow rates range from less than 1 to more than 10 L/min. The present porcine model study was aimed at determining the impact of varying sweep gas flow rates on CO2 removal under different blood flow conditions and membrane lung surface areas. Two different membrane lungs, with surface areas of 0.4 and 0.8m2, were used in nine pigs with experimentally-induced hypercapnia. During each experiment, the blood flow was increased stepwise from 300 to 900 mL/min, with further increases up to 1800 mL/min with the larger membrane lung in steps of 300 mL/min. Sweep gas was titrated under each condition from 2 to 8 L/min in steps of 2 L/min. Extracorporeal CO2 elimination was normalized to a PaCO2 of 45 mmHg before the membrane lung. Reversal of hypercapnia was only feasible when blood flow rates above 900 mL/min were used with a membrane lung surface area of at least 0.8m2. The membrane lung with a surface of 0.4m2 allowed a maximum normalized CO2 elimination rate of 41 ± 6 mL/min with 8 L/min sweep gas flow and 900 mL blood flow/min. The increase in sweep gas flow from 2 to 8 L/min increased normalized CO2 elimination from 35 ± 5 to 41 ± 6 with 900 mL blood flow/min, whereas with lower blood flow rates, any increase was less effective, levelling out at 4 L sweep gas flow/min. The membrane lung with a surface area of 0.8m2 allowed a maximum normalized CO2 elimination rate of 101 ± 12 mL/min with increasing influence of sweep gas flow. The delta of normalized CO2 elimination increased from 4 ± 2 to 26 ± 7 mL/min with blood flow rates being increased from 300 to 1800 mL/min, respectively. The influence of sweep gas flow on the CO2 removal capacity of ECCO2R systems depends predominantly on blood flow rate and membrane lung surface area. In this model, considerable CO2 removal occurred only with the larger membrane lung surface of 0.8m2 and when blood flow rates of ≥ 900 mL/min were used.

Pathogenic enteric bacteria aspirated from the oropharynx are the main cause of ventilator-associated pneumonia (VAP). Using chlorhexidine (CHX) orally or selective decontamination has been shown to reduce VAP. In a pilot study we found that oral care with the probiotic bacterium Lactobacillus plantarum 299 (Lp299) was as effective as CHX in reducing enteric bacteria in the oropharynx. To confirm those results, in this expanded study with an identical protocol we increased the number of patients and participating centres. One hundred and fifty critically ill patients on mechanical ventilation were randomised to oral care with either standard 0.1% CHX solution (control group) or a procedure comprising final application of an emulsion of Lp299. Samples for microbiological analyses were taken from the oropharynx and trachea at inclusion and subsequently at defined intervals. Student’s t test was used for comparisons of parameters recorded daily and Fisher’s exact test was used to compare the results of microbiological cultures. Potentially pathogenic enteric bacteria not present at inclusion were identified in oropharyngeal samples from 29 patients in the CHX group and in 31 samples in the probiotic group. Considering cultures of tracheal secretions, enteric bacteria were found in 17 and 19 samples, respectively. Risk ratios show a difference in favour of the Lp group for fungi in oropharyngeal cultures. VAP was diagnosed in seven patients in the Lp group and in 10 patients among the controls. In this multicentre study, we could not demonstrate any difference between Lp299 and CHX used in oral care procedures regarding their impact on colonisation with emerging potentially pathogenic enteric bacteria in the oropharynx and trachea. ClinicalTrials.gov, NCT01105819 . Registered on 9 April 2010. First part: Current Controlled Trials, ISRCTN00472141 . Registered on 22 November 2007 (published Critical Care 2008, 12:R136).

Veno-venous extracorporeal CO2 removal (vv-ECCO2R) is increasingly being used in the setting of acute respiratory failure. Blood flow rates through the device range from 200 ml/min to more than 1500 ml/min, and the membrane surface areas range from 0.35 to 1.3 m2. The present study in an animal model with similar CO2 production as an adult patient was aimed at determining the optimal membrane lung surface area and technical requirements for successful vv-ECCO2R. Four different membrane lungs, with varying lung surface areas of 0.4, 0.8, 1.0, and 1.3m2 were used to perform vv-ECCO2R in seven anesthetized, mechanically ventilated, pigs with experimentally induced severe respiratory acidosis (pH 7.0–7.1) using a 20Fr double-lumen catheter with a sweep gas flow rate of 8 L/min. During each experiment, the blood flow was increased stepwise from 250 to 1000 ml/min. Amelioration of severe respiratory acidosis was only feasible when blood flow rates from 750 to 1000 ml/min were used with a membrane lung surface area of at least 0.8 m2. Maximal CO2 elimination was 150.8 ml/min, with pH increasing from 7.01 to 7.30 (blood flow 1000 ml/min; membrane lung 1.3 m2). The membrane lung with a surface of 0.4 m2 allowed a maximum CO2 elimination rate of 71.7 mL/min, which did not result in the normalization of pH, even with a blood flow rate of 1000 ml/min. Also of note, an increase of the surface area above 1.0 m2 did not result in substantially higher CO2 elimination rates. The pressure drop across the oxygenator was considerably lower (<10 mmHg) in the largest membrane lung, whereas the smallest revealed a pressure drop of more than 50 mmHg with 1000 ml blood flow/min. In this porcine model, vv-ECCO2R was most effective when using blood flow rates ranging between 750 and 1000 ml/min, with a membrane lung surface of at least 0.8 m2. In contrast, low blood flow rates (250–500 ml/min) were not sufficient to completely correct severe respiratory acidosis, irrespective of the surface area of the membrane lung being used. The converse was also true, low surface membrane lungs (0.4 m2) were not capable of completely correcting severe respiratory acidosis across the range of blood flows used in this study.

Monitoring of lung function is essential to assess changes in the lung condition, and to correct and improve ventilator and adjuvant therapies in acute respiratory distress syndrome (ARDS). In this review we discuss the use of monitoring of gas exchange, lung mechanics and shortly on lung imaging in this condition.

Ventilation treatment of acute lung injury (ALI) requires the application of positive airway pressure at the end of expiration (PEEP_app) to avoid lung collapse. However, the total pressure exerted on the alveolar walls (PEEP_tot) is the sum of PEEP_app and intrinsic PEEP (PEEP_i), a hidden component. To measure PEEP_tot, ventilation must be discontinued with an end-expiratory hold maneuver (EEHM). We hypothesized that artificial neural networks (ANN) could estimate the PEEP_tot from flow and pressure tracings during ongoing mechanical ventilation. Ten pigs were mechanically ventilated, and the time constant of their respiratory system (τ_RS) was measured. We shortened their expiratory time (TE) according to multiples of τ_RS, obtaining different respiratory patterns (R_pat). Pressure (P_AW) and flow (V′_AW) at the airway opening during ongoing mechanical ventilation were simultaneously recorded, with and without the addition of external resistance. The last breath of each R_pat included an EEHM, which was used to compute the reference PEEP_tot. The entire protocol was repeated after the induction of ALI with i.v. injection of oleic acid, and 382 tracings were obtained. The ANN had to extract the PEEP_tot, from the tracings without an EEHM. ANN agreement with reference PEEP_tot was assessed with the Bland–Altman method. Bland Altman analysis of estimation error by ANN showed −0.40 ± 2.84 (expressed as bias ± precision) and ±5.58 as limits of agreement (data expressed as cmH₂O). The ANNs estimated the PEEP_tot well at different levels of PEEP_app under dynamic conditions, opening up new possibilities in monitoring PEEP_i in critically ill patients who require ventilator treatment.

Introduction: Low tidal volume (V_T) ventilation is recommended in patients with acute respiratory distress syndrome (ARDS). This may increase arterial carbon dioxide tension (PaCO₂), decrease pH, and augment pulmonary vascular resistance (PVR). We hypothesized that Tris(hydroxymethyl)aminomethane (THAM), a pure proton acceptor, would dampen these effects, preventing the increase in PVR. Methods: A one-hit injury ARDS model was established by repeated lung lavages in 18 piglets. After ventilation with V_T of 6 ml/kg to maintain normocapnia, V_T was reduced to 3 ml/kg to induce hypercapnia. Six animals received THAM for 1 h, six for 3 h, and six serving as controls received no THAM. In all, the experiment continued for 6 h. The THAM dosage was calculated to normalize pH and exhibit a lasting effect. Gas exchange, pulmonary, and systemic hemodynamics were tracked. Inflammatory markers were obtained at the end of the experiment. Results: In the controls, the decrease in V_T from 6 to 3 ml/kg increased PaCO₂ from 6.0±0.5 to 13.8±1.5 kPa and lowered pH from 7.40±0.01 to 7.12±0.06, whereas base excess (BE) remained stable at 2.7±2.3 mEq/L to 3.4±3.2 mEq/L. In the THAM groups, PaCO₂ decreased and pH increased above 7.4 during the infusions. After discontinuing the infusions, PaCO₂ increased above the corresponding level of the controls (15.2±1.7 kPa and 22.6±3.3 kPa for 1-h and 3-h THAM infusions, respectively). Despite a marked increase in BE (13.8±3.5 and 31.2±2.2 for 1-h and 3-h THAM infusions, respectively), pH became similar to the corresponding levels of the controls. PVR was lower in the THAM groups (at 6 h, 329±77 dyn∙s/m⁵ and 255±43 dyn∙s/m⁵ in the 1-h and 3-h groups, respectively, compared with 450±141 dyn∙s/m⁵ in the controls), as were pulmonary arterial pressures. Conclusions: The pH in the THAM groups was similar to pH in the controls at 6 h, despite a marked increase in BE. This was due to an increase in PaCO₂ after stopping the THAM infusion, possibly by intracellular release of CO₂. Pulmonary arterial pressure and PVR were lower in the THAM-treated animals, indicating that THAM may be an option to reduce PVR in acute hypercapnia.

Ventilator settings resulting in decreased driving pressure (ΔP) are positively associated with survival. How to further foster the potential beneficial mediator effect of a reduced ΔP? One possibility is promoting the active modification of the lung’s “mechanical scenario” by means of lung recruitment and positive end-expiratory pressure selection. By taking into account the individual distribution of the threshold-opening airway pressures to achieve maximal recruitment, a redistribution of the tidal volume from overdistended to newly recruited lung occurs. The resulting more homogeneous distribution of transpulmonary pressures may induce a relief of overdistension in the upper regions. The gain in lung compliance after a successful recruitment rescales the size of the functional lung, potentially allowing for a further reduction in ΔP.