PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study.

BACKGROUND: Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low-density lipoprotein receptor re-uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. METHODS: Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman's coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28- and 90-day mortality. RESULTS: Median plasma PCSK9 levels were 278 [182-452] ng mL-1 on day 1. PCSK9 correlated positively with PTX3 at the three time-points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28- and 90-day mortality rate as compared to other quartiles. CONCLUSION: In our sub-analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

Acute renal response to changes in carbon dioxide in mechanically ventilated female pigs.

Kidney response to acute and mechanically induced variation in ventilation associated with different levels of PEEP has not been investigated. We aimed to quantify the effect of ventilatory settings on renal acid-base compensation. Forty-one pigs undergoing hypo- (<0.2 Lkg-1 min-1, PEEP 25 cmH2O), intermediate (0.2-0.4 Lkg-1 min-1 with either PEEP 5 or 25 cmH2O), or hyper-ventilation (>0.4 Lkg-1 min-1, PEEP 5 cmH2O) for 48 h were retrospectively included. The decrease in pH paralleled the decrease in plasma strong ion difference (SID) in hyper- and intermediately ventilated groups with lower PEEP. In contrast, the plasma SID remained nearly constant in hypo- and intermediately ventilated groups with higher PEEP. Changes in plasma chloride concentration accounted for the changes in plasma SID (conditional R2 = 0.86). The plasma SID changes were paralleled by mirror changes in urinary SID. Higher PEEP (25 cmH2O), compared to lower PEEP (5 cmH2O) dampened or abolished the renal compensation through its effect on hemodynamics (higher central venous and mean pulmonary pressures), irrespective of minute ventilation. During mechanical ventilation, the compensatory renal response to respiratory derangement is immediate and progressive but can be dampened by high PEEP levels.

Effects of hyperoxemia in patients with sepsis - A post-hoc analysis of a multicentre randomized clinical trial.

BACKGROUND: Administration of supplemental oxygen is a life-saving treatment in critically ill patients. Still, optimal dosing remains unclear during sepsis. The aim of this post-hoc analysis was to assess the association between hyperoxemia and 90-day mortality in a large cohort of septic patients. METHODS: This is a post-hoc analysis of the Albumin Italian Outcome Sepsis (ALBIOS) randomized controlled trial (RCT). Patients with sepsis who survived the first 48 h since randomization were included and stratified into two groups according to their average PaO2 levels during the first 48 h (PaO2 0-48 h). The cut-off value was established at 100 mmHg (average PaO2 0-48 h >100 mmHg: hyperoxemia group; PaO2 0-48h≤100: normoxemia group). The primary outcome was 90-day mortality. RESULTS: 1632 patients were included in this analysis (661 patients in the hyperoxemia group, 971 patients in the normoxemia group). Concerning the primary outcome, 344 (35.4%) patients in the hyperoxemia group vs. 236 (35.7%) in the normoxemia group had died within 90 days from randomization (p = 0.909). No association was found after adjusting for confounders (HR 0.87; CI [95%] 0.736-1.028, p = 0.102) or after excluding patients with hypoxemia at enrollment, patients with lung infection or including post-surgical patients only. Conversely, we found an association between lower risk of 90-day mortality and hyperoxemia in the subgroup including patients who had the lung as primary site of infection (HR 0.72; CI [95%] 0.565-0.918). Mortality at 28 days, ICU mortality, incidence of acute kidney injury, use of renal replacement therapy, days to suspension of vasopressor or inotropic agents, and resolution of primary and secondary infections did not differ significantly. Duration of mechanical ventilation and length of stay in ICU were significantly longer in patients with hyperoxemia. CONCLUSIONS: In a post-hoc analysis of a RCT enrolling septic patients, hyperoxemia as average PaO2>100 mmHg during the first 48 h was not associated with patients' survival.

Transient paraplegia due to subarachnoid haemorrhage following spinal anaesthesia.

Spinal subarachnoid haemorrhage is a rare complication of spinal anaesthesia, especially following atraumatic lumbar puncture and in the absence of coagulopathies. The initial presentation of spinal subarachnoid haemorrhage is variable and paraplegia with full recovery within a few hours is rare. Bleeding can extend into the intracranial subarachnoid space, but there are only a few reports of symptomatic intracranial and spinal subarachnoid haemorrhage after spinal anaesthesia. We report co-existing spinal subarachnoid haemorrhage and intracranial subarachnoid haemorrhage after atraumatic spinal anaesthesia in a 69-year-old woman without a coagulopathy. The day after surgery she developed flaccid paraplegia that spontaneously resolved in a few hours. Magnetic resonance imaging demonstrated subarachnoid high signal intensity from T11-S2, consistent with spinal subarachnoid haemorrhage. On the same day the patient complained of severe headache which was later followed by diplopia. Neurological imaging studies revealed diffuse distribution of blood in the subarachnoid space but no intracranial vascular malformations. At the time of diagnosis spontaneous recovery of spinal symptoms had already begun and the clinical manifestations eventually resolved with conservative management. The possibility of an intracranial haemorrhage should always be considered when spinal subarachnoid haemorrhage is identified, even in cases of uncomplicated spinal anaesthesia in patients with no known risk factors for spinal haemorrhage.

In vivo conditioning of acid-base equilibrium by crystalloid solutions: an experimental study on pigs.

PURPOSE: Large infusion of crystalloids may induce acid-base alterations according to their strong ion difference ([SID]). We wanted to prove in vivo, at constant PCO(2), that if the [SID] of the infused crystalloid is equal to baseline plasma bicarbonate, the arterial pH remains unchanged, if lower it decreases, and if higher it increases. METHODS: In 12 pigs, anesthetized and mechanically ventilated at PCO(2) ≈40 mmHg, 2.2 l of crystalloids with a [SID] similar to (lactated Ringer's 28.3 mEq/l), lower than (normal saline 0 mEq/l), and greater than (rehydrating III 55 mEq/l) baseline bicarbonate (29.22 ± 2.72 mEq/l) were infused for 120 min in randomized sequence. Four hours of wash-out were allowed between the infusions. Every 30 min up to minute 120 we measured blood gases, plasma electrolytes, urinary volume, pH, and electrolytes. Albumin, hemoglobin, and phosphates were measured at time 0 and 120 min. RESULTS: Lactated Ringer's maintained arterial pH unchanged (from 7.47 ± 0.06 to 7.47 ± 0.03) despite a plasma dilution around 12%. Normal saline caused a reduction in pH (from 7.49 ± 0.03 to 7.42 ± 0.04) and rehydrating III induced an increase in pH (from 7.46 ± 0.05 to 7.49 ± 0.04). The kidney reacted to the infusion, minimizing the acid-base alterations, by increasing/decreasing the urinary anion gap, primarily by changing sodium and chloride concentrations. Lower urine volume after normal saline infusion was possibly due to its greater osmolarity and chloride concentration as compared to the other solutions. CONCLUSIONS: Results support the hypothesis that at constant PCO(2), pH changes are predictable from the difference between the [SID] of the infused solution and baseline plasma bicarbonate concentration.

Kidney instant monitoring (K.IN.G): a new analyzer to monitor kidney function.

AIM: The key role of the kidney in the regulation of body fluids and acid-base status is well known. Nonetheless, urine analysis has not received great attention in critically ill patients, likely due to the common practice of only analyzing 24-hour collected specimens. We hypothesized that the kidney may react more rapidly to minimal hemodynamic and acid-base status variations than can be assessed by a 24-hour analysis. Accordingly, we developed and tested a urine analyzer, allowing quasi-continuous urinary analysis. METHODS: A novel analyzer (Kidney INstant monitorinG--K.IN.G) was developed that allows non-invasive, quasi-continuous analysis of urine pH, sodium, chloride, potassium and ammonium levels. Analytic measurement accuracy was calculated for urine samples of patients admitted to ICUs as well as medical staff, using standard techniques as references. For clinical investigation, approximately 200 patients were connected to the analyzer after ICU admission until discharge. Clinically relevant parameters were recorded. Here, three cases are presented. RESULTS: For each analytic parameter, the accuracy of measurements obtained with the K.IN.G analyzer appeared to be acceptable as compared to those of the reference techniques. In case 1, urine analysis revealed increased urinary sodium and chloride excretion strictly in parallel with mean arterial pressure, and increased ammonium excretion which was associated with moderate hypercapnia. Case 2 showed increases in urinary pH and sodium and chloride levels following awakening after sedation suspension. In case 3, urine analysis revealed an impairment of renal concentrative power, which was associated with hypovolemia. CONCLUSION: The K.IN.G analyzer, allowing quasi-continuous monitoring of urinary pH and principal electrolyte levels, may represent a novel tool for clinical and research purposes.

The ratio between arterio-venous PCO2 difference and arterio-jugular oxygen difference as estimator of critical cerebral hypoperfusion.

AIM: The aim of this study was to evaluate the arterio-venous difference in carbon dioxide tension (DPCO2) and the ratio between DPCO2 and arterio-jugular oxygen difference (AJDO2) as indicators of compensated or uncompensated cerebral hypoperfusion. METHODS: Cerebral blood flow (CBF) was reduced stepwise in 6 pigs by inducing intracranial hypertension with consequently cerebral perfusion pressure (CPP) reduction: CBF 100%, 50-60 % of baseline, 20-30% of baseline. Intracranial pressure (ICP), mean arterial pressure (MAP), CPP and CBF (laser-Doppler method) were continuously recorded. Superior sagittal sinus was punctured for the determination of AJDO2 and DPCO2. RESULTS: CBF impairment was accompanied by changes in AJDO2 from 6.03 +/- 1.21 vol% to 7.32 +/- 1.30 vol%, up to 8.07 +/- 1.32 vol% (P < 0.01), in DPCO2 from 12.17 +/- 3.25 mmHg to 16 +/- 4.12 mmHg, up to 26.5 +/- 6.41 mmHg (P < 0.01), and DPCO2/AJDO2 ratio from 2.05 +/- 0.39 to 2.06 +/- 0.72 up to 3.41 +/- 1.09 in the 3 phases (P < 0.05). CONCLUSIONS: When CBF declines AJDO2 increases, indicating greater extraction of O2 to satisfy aerobic metabolism. However, this mechanism can no longer compensate once a critical CBF threshold is reached. DPCO2 rises slowly during moderate CBF reduction because of defective washout; the rise is steeper during marked CBF impairment when anaerobic metabolism takes place. During cerebral hypoperfusion the venous blood gases and acid base variables mirror the degree of cerebral perfusion. In particular the DPCO2, and the DPCO2/ AJDO2 ratio may be useful markers of critical brain hypoperfusion.

Pulmonary and extrapulmonary forms of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is usually viewed as the functional and morphological expression of a similar underlying lung injury caused by a variety of insults. However, the distinction between ARDS due to a direct (ARDSp) versus an indirect (ARDSexp) lung injury is gaining more attention as a means of better comprehending the pathophysiology of ARDS and for modifying ventilatory management. From the few published studies, we can summarize that: (1) the prevalent damage in early stages of a direct insult is intra-alveolar, whereas in indirect injury it is the interstitial edema. It is possible that the two insults may coexist (i.e., one lung with direct injury (as in pneumonia) and the other with indirect injury, through mediator release from the contralateral pneumonia); (2) the radiological pattern, by chest x-ray or computed tomography (CT), is different in ARDSp (characterized by prominent consolidation) and ARDSexp (characterized by prominent ground-glass opacification); (3) in ARDSp lung elastance is more markedly increased than in ARDSexp, where the main abnormality is the increase in chest wall elastance, due to abnormally high intra-abdominal pressure; (4) positive end-expiratory pressure (PEEP), inspiratory recruitment, and prone position are more effective to improve respiratory mechanics, alveolar recruitment, and gas-exchange in ARDSexp. Further studies are warranted to better define if the distinction between ARDS of different origins can improve clinical management and survival.

Pathophysiology of prone positioning in the healthy lung and in ALI/ARDS.

Prone position was initially introduced in healthy anesthetized and paralyzed subjects for surgical specific reasons. Then, it was used during acute respiratory failure to improve gas exchange. The interest on prone position during ALI/ARDS progressively increased, even if the mechanisms leading to a respiratory improvement are not yet completely understood. In normal subjects, during anesthesia and paralysis, prone position determines a more homogeneous distribution of the gravitational gradient of alveolar inflation, a ventilation distributed towards the non dependent lung regions and a reverse of the gravitational distribution of regional perfusion, even if factors other than gravity are involved. Moreover, prone position causes, both in healthy subject and in obese patients, an improvement in oxygenation and in functional residual capacity without affecting respiratory system, lung and chest wall compliance. In ALI/ARDS patients, prone position lead to a reverse of the alveolar inflation and ventilation distribution, due to the reverse of hydrostatic pressure overlying lung parenchyma, the reverse of heart weight, and the changes in chest wall shape and mechanical properties. Little data are available for the modifications in regional lung perfusion. The possible mechanisms involved in oxygenation improvement during prone position in ALI/ARDS patients are: 1) increased lung volumes; 2) redistribution of lung perfusion; 3) recruitment of dorsal spaces with more homogeneous ventilation and perfusion distribution. From a clinical point of view, prone position seems to be a very promising treatment for ALI/ARDS, even if its use is not yet a standard clinical practice. We have recently finished a randomized-controlled trial in order to investigate the clinical impact of this procedure. In the preliminary phase of the study performed in 35 Italian Intensive Care Units, we studied, from 1996 to 1998, 73 patients with a PaO2/FiO2 of 123 +/- 42 and a SAPS (Simplified Acute Physiology Score) of 38 +/- 11. After the first hour of prone positioning, the PaO2/FiO2 ratio of 76% of the patients had increased by more than 20 mmHg (responder) with a mean increase of 78 +/- 53 mmHg. The proportion of responders increased to 85% after 6 hours of prone positioning. The incidence of maneuver-related complications and severe and life-threatening complications was extremely rare. The overall mortality at ICU discharge was 51% and the ICU stay was similar in survivors and non survivors (17.8 +/- 11.6 vs 17.8 +/- 11.4 days).

[Positive end expiratory pressure in anesthesia]. / Pressione positiva di fine espirazione in anestesia.

It is well established that general anesthesia, with or without paralysis, causes profound changes in respiratory function. From a clinical point of view, the more important consequence of this impairment is a decreased efficiency of gas exchange, with a decreased blood oxygenation. The main reason of this respiratory embarrassment is the intraoperative occurrence of atelectasis, mainly in the dependent lung regions. The amount of atelectasis, computed through Computerized Tomography, correlates with the amount of intrapulmonary shunt; thus, alveolar collapse and ventilation/perfusion mismatching are considered the most important factors for poor respiratory function. This deterioration seems also to play a crucial role in obese patients, who have poorer respiratory function and gas exchange than normal subjects already in physiological conditions. Different ventilatory approaches have been tried to resolve and eventually prevent the anesthesia-induced atelectasis. In normal subjects, the sole application of positive end-expiratory pressure (PEEP) seems to be an useless tool for improving gas exchange, probably because of changes in hemodynamics functions. The only effective application of PEEP seems to be in association to an alveolar recruitment manoeuvre. As the anesthesia-induced atelectasis are also present in the postoperative period, this ventilatory approach may also be used to prevent this condition. In obese patients PEEP seems to have a major effectiveness than in normal subjects, with an improvement of lung volumes, respiratory mechanics, gas exchange and an occurrence of recruitment. However, further studies are necessary to define optimal value of PEEP and tidal volume for different types of patients.