Lung volumes, respiratory mechanics and dynamic strain during general anaesthesia.

BACKGROUND: Driving pressure (ΔP) represents tidal volume normalised to respiratory system compliance (CRS) and is a novel parameter to target ventilator settings. We conducted a study to determine whether CRS and ΔP reflect aerated lung volume and dynamic strain during general anaesthesia. METHODS: Twenty non-obese patients undergoing open abdominal surgery received three PEEP levels (2, 7, or 12 cm H2O) in random order with constant tidal volume ventilation. Respiratory mechanics, lung volumes, and alveolar recruitment were measured to assess end-expiratory aerated volume, which was compared with the patient's individual predicted functional residual capacity in supine position (FRCp). RESULTS: CRS was linearly related to aerated volume and ΔP to dynamic strain at PEEP of 2 cm H2O (intraoperative FRC) (r=0.72 and r=0.73, both P<0.001). These relationships were maintained with higher PEEP only when aerated volume did not overcome FRCp (r=0.73, P<0.001; r=0.54, P=0.004), with 100 ml lung volume increases accompanied by 1.8 ml cm H2O-1 (95% confidence interval [1.1-2.5]) increases in CRS. When aerated volume was greater or equal to FRCp (35% of patients at PEEP 2 cm H2O, 55% at PEEP 7 cm H2O, and 75% at PEEP 12 cm H2O), CRS and ΔP were independent from aerated volume and dynamic strain, with CRS weakly but significantly inversely related to alveolar dead space fraction (r=-0.47, P=0.001). PEEP-induced alveolar recruitment yielded higher CRS and reduced ΔP only at aerated volumes below FRCp (P=0.015 and 0.008, respectively). CONCLUSIONS: During general anaesthesia, respiratory system compliance and driving pressure reflect aerated lung volume and dynamic strain, respectively, only if aerated volume does not exceed functional residual capacity in supine position, which is a frequent event when PEEP is used in this setting.

Early-goal directed therapy for septic shock: is it the end?

Three randomized clinical trials have recently provided data on the lack of effectiveness of "early-goal directed therapy" (EGDT) (i.e. optimization of tissue oxygenation in the first 6 hours since sepsis diagnosis using different therapeutic interventions based on the assessment of the central venous oxygen saturation to titrate such interventions) in the initial management of patients with septic shock. In a first trial including 31 US hospitals (the ProCESS study, N.=1341), three different therapeutic strategies (EGDT vs. protocol-based therapy vs. usual care) were compared and no difference in the primary endpoint (60-day mortality) was found (EGDT 21%, protocol-based therapy 18% and usual care 19%). No significant difference in death by 90 days or in other secondary outcomes, including serious adverse events, was found, as well. A second trial (ARISE, N.=1600), mostly conducted in Australia and New Zealand, randomized patients to EGDT or usual care. Ninety-day mortality was similar between groups (19% vs. 19%, respectively; P=0.90) and no other differences in secondary endpoints were recorded between the two groups. A third study (ProMISe, N.=1260) included patients in 56 hospitals across England, randomly assigned to EGDT or usual care. By 90 days, mortality was similar between groups (29% vs. 29%, respectively; P=0.90). Moreover, EGDT significantly increased costs and was associated with a longer hospital length of stay. We discussed some issues related to the differences between these studies and the pivotal paper from Rivers et al. and how EGDT should be still considered in the treatment of sepsis.

How to target temperature after cardiac arrest: insights from a randomized clinical trial.

Implementation of treatments able to improve survival and neurological recovery of cardiac arrest (CA) survivors is a major clinical challenge. More than ten years ago, two pivotal trials showed that application of therapeutic hypothermia (TH, 32-34 °C) to patients resuscitated from an out-of-hospital CA (OHCA) with an initial shockable rhythm significantly ameliorated their outcome. Since then, TH has been used also for non-shockable rhythms and for in-hospital CA to some extent, even if the quality of evidence supporting TH in such situations remained very low. The objective of this randomized, controlled, multicenter study (named "Targeted Temperature Management" TTM study) was to compare two different strategies of temperature control after CA; patients were randomized to be treated either at 33 °C or at 36 °C for 24 hours, while fever was accurately avoided for the first 3 days since randomization. Inclusion criteria were: Glasgow Coma Score <8, presumed cardiac origin of arrest, randomization occurring within the first 4 hours from the return of spontaneous circulation. Patients were excluded if they had an unwitnessed arrest with asystole as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke, and a body temperature of less than 30 °C. A specific algorithm was used to decide for withdrawal of care in patients remaining comatose after 72 hours since normothermia was achieved. The primary outcome was 6-month mortality. After the enrollment of 939 patients, the authors did not find any significant difference between groups in primary outcome (235/473 [50%] and 225/466 [48%] of patients died in 33 °C and 36 °C group, respectively; HR for death if in the 33 °C group, 1.06 [95% CI 0.89 to 1.28; P=0.51]). Similarly, the analysis of the composite outcome of death or poor neurologic function yielded similar results between the two groups. This is the largest study evaluating the effects of two different strategies of temperature management after CA. Some important concerns have been raised on the real benefit of keeping CA patients at 33 °C and major changes in clinical practice are expected. We discussed herein the main differences with previous randomized trials and tried to identify possible explanations for these findings.

Esmolol for septic shock: more than just heart rate control?

Excessive adrenergic stimulation may be associated with several adverse events and contribute to increase mortality in critically ill septic patients. Few clinical data exist on the effects of adrenergic blockade in this setting. The objective of this study was to investigate the effect of a short acting b-blocker (esmolol) in septic shock patients. In a single-center, controlled, open-label, phase 2 trial (from November 2010 to July 2012), Morelli et al. randomized patients with a need of norepinephrine to maintain a mean arterial pressure above 65 mmHg to receive either esmolol or standard of care. Patients were included if, after 24 hours of initial resuscitation, hypovolemia was excluded (wedge pressure ≥12 mmHg or central venous pressure ≥8 mmHg) and heart rate was above 95 bpm. Patients were excluded if they were younger than 18 years, had previous b-blockers therapy, cardiac index was ≤2.2 L/min/m² with wedge pressure >18 mmHg, were diagnosed with significant cardiac valvular diseases or were pregnant. The primary outcome was the reduction in heart rate between 80 and 94 bpm over a 96-hr period. Secondary outcomes included norepinephrine requirement, hemodynamic changes, organ function, adverse events and 28-day mortality. A total of 154 patients, 77 for each group, were enrolled. Esmolol was more effective than standard treatment to reduce heart rate within target limits; also, b-blocker therapy was associated with an increased stroke volume and left ventricular work index when compared to the control group. These favorable hemodynamic effects were associated with a better control of lactate levels, a higher reduction in norepinephrine and fluids requirement. Mortality was 49.4% in the esmolol group and 80.5% in the control group (P<0.01). This is the first study showing an improvement in cardiac function and 28-day mortality in septic patients adding b-blockers to standard therapy. We discussed several statistical and methodological limitations that may influence the generability of these results.

Sedation after cardiac arrest and during therapeutic hypothermia.

Mild therapeutic hypothermia (MTH) has improved neurological outcome of comatose patients after cardiac arrest (CA). Since the first clinical studies performed in this setting, sedation has always been associated with cooling procedures. The use of sedative drugs during MTH is required because it allows faster achievement and better maintenance of target temperature. Further studies are necessary to prove any potential neuroprotective effects of sedation after CA. No differences in clinical outcomes have been found among different drugs, except for those related to their intrinsic pharmacological properties: the association propofol/remifentanil provides a faster recovery of consciousness than midazolam/fentanyl but is associated with the need of more vasopressors to maintain stable hemodynamic. Moreover, pharmacokinetic properties of these drugs are often altered during MTH so that standard drug regimens could result in overdosing because of reduced clearance. Neuromonitoring could be helpful to titrate drugs' effects and detect earlier complications (i.e. seizure), while a wake-up test should be avoided during the first 24 hours after CA.