Elio Antonucci

Myocardial depression in sepsis: From pathogenesis to clinical manifestations and treatment

The cardiovascular system plays a key role in sepsis, and septic myocardial depression is a common finding associated with increased morbidity and mortality. Myocardial depression during sepsis is not clearly defined, but it can perhaps be best described as a global (systolic and diastolic) dysfunction of both the left and right sides of the heart. The pathogenesis of septic myocardial depression involves a complex mix of systemic (hemodynamic) factors and genetic, molecular, metabolic, and structural alterations. Pulmonary artery catheterization and modern echo-Doppler techniques are important diagnostic tools in this setting. There are no specific therapies for septic myocardial depression, and the cornerstone of management is control of the underlying infectious process (adequate antibiotic therapy, removal of the source) and hemodynamic stabilization (fluids, vasopressor and inotropic agents). In this review, we will summarize the pathogenesis, diagnosis, and treatment of myocardial depression in sepsis. Additional studies are needed in order to improve diagnosis and identify therapeutic targets in septic myocardial dysfunction.

The relation between the incidence of hypernatremia and mortality in patients with severe traumatic brain injury

IntroductionThe study was aimed at verifying whether the occurrence of hypernatremia during the intensive care unit (ICU) stay increases the risk of death in patients with severe traumatic brain injury (TBI). We performed a retrospective study on a prospectively collected database including all patients consecutively admitted over a 3-year period with a diagnosis of TBI (post-resuscitation Glasgow Coma Score ≤ 8) to a general/neurotrauma ICU of a university hospital, providing critical care services in a catchment area of about 1,200,000 inhabitants.MethodsDemographic, clinical, and ICU laboratory data were prospectively collected; serum sodium was assessed an average of three times per day. Hypernatremia was defined as two daily values of serum sodium above 145 mmol/l. The major outcome was death in the ICU after 14 days. Cox proportional-hazards regression models were used, with time-dependent variates designed to reflect exposure over time during the ICU stay: hypernatremia, desmopressin acetate (DDAVP) administration as a surrogate marker for the presence of central diabetes insipidus, and urinary output. The same models were adjusted for potential confounding factors.ResultsWe included in the study 130 TBI patients (mean age 52 years (standard deviation 23); males 74%; median Glasgow Coma Score 3 (range 3 to 8); mean Simplified Acute Physiology Score II 50 (standard deviation 15)); all were mechanically ventilated; 35 (26.9%) died within 14 days after ICU admission. Hypernatremia was detected in 51.5% of the patients and in 15.9% of the 1,103 patient-day ICU follow-up. In most instances hypernatremia was mild (mean 150 mmol/l, interquartile range 148 to 152). The occurrence of hypernatremia was highest (P = 0.003) in patients with suspected central diabetes insipidus (25/130, 19.2%), a condition that was associated with increased severity of brain injury and ICU mortality. After adjustment for the baseline risk, the incidence of hypernatremia over the course of the ICU stay was significantly related with increased mortality (hazard ratio 3.00 (95% confidence interval: 1.34 to 6.51; P = 0.003)). However, DDAVP use modified this relation (P = 0.06), hypernatremia providing no additional prognostic information in the instances of suspected central diabetes insipidus.ConclusionsMild hypernatremia is associated with an increased risk of death in patients with severe TBI. In a proportion of the patients the association between hypernatremia and death is accounted for by the presence of central diabetes insipidus.

β-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study

Most adult patients receiving extracorporeal membrane oxygenation (ECMO) require antibiotic therapy, however the pharmacokinetics of β-lactams have not been well studied in these conditions. In this study, data from all patients receiving ECMO support and meropenem (MEM) or piperacillin/tazobactam (TZP) were reviewed. Drug concentrations were measured 2h after the start of a 30-min infusion and just before the subsequent dose. Therapeutic drug monitoring (TDM) results in ECMO patients were matched with those in non-ECMO patients for (i) drug regimen, (ii) renal function, (iii) total body weight, (iv) severity of organ dysfunction and (v) age. Drug concentrations were considered adequate if they remained 4-8× the clinical MIC breakpoint for Pseudomonas aeruginosa for 50% (TZP) or 40% (MEM) of the dosing interval. A total of 41 TDM results (27 MEM; 14 TZP) were obtained in 26 ECMO patients, with 41 matched controls. There were no significant differences in serum concentrations or pharmacokinetic parameters between ECMO and non-ECMO patients, including Vd [0.38 (0.27-0.68) vs. 0.46 (0.33-0.79)L/kg; P=0.37], half-life [2.6 (1.8-4.4) vs. 2.9 (1.7-3.7)h; P=0.96] and clearance [132 (66-200) vs. 141 (93-197)mL/min; P=0.52]. The proportion of insufficient (13/41 vs. 12/41), adequate (15/41 vs. 19/41) and excessive (13/41 vs. 10/41) drug concentrations was similar in ECMO and non-ECMO patients. Achievement of target concentrations of these β-lactams was poor in ECMO and non-ECMO patients. The influence of ECMO on MEM and TZP pharmacokinetics does not appear to be significant.

Cerebral blood flow decreases during intermittent hemodialysis in patients with acute kidney injury, but not in patients with end-stage renal disease

BACKGROUND Cerebral blood flow (CBF) may decrease during intermittent hemodialysis (IHD). Patients with acute kidney injury (AKI) may be more vulnerable to cerebral hypoperfusion than patients with end-stage renal disease (ESRD), due to concomitant critical illness and hemodynamic instability. METHODS In this observational, prospective study, we measured mean flow velocity at the level of the middle cerebral artery by transcranial Doppler at the start, after 2 h and at the end of a hemodialysis session in 15 consecutive patients with AKI and critical illness referred to the nephrological intensive care unit of a university hospital and in 12 patients with ESRD on regular treatment thrice weekly, who served as controls. We compared end-dialysis changes from baseline in mean flow velocity between the study groups and examined the correlation between this change and that of other relevant clinical parameters. RESULTS Mean flow velocity decreased significantly at end-dialysis in the patients with AKI, but not in those with ESRD (P = 0.02). This difference persisted after adjusting for baseline mean flow velocity and net ultrafiltration volume. No significant correlations were found in either group between changes in mean flow velocity and changes in mean blood pressure (AKI: r = -0.27, P = 0.34; ESRD: r = 0.15, P = 0.68), SUN (AKI: r = -0.33, P = 0.25; ESRD: r = 0.06, P = 0.85), plasma HCO(3)(-) (AKI: r = -0.52, P = 0.24; ESRD: r = -0.18, P = 0.59), hematocrit (AKI: r = 0.08, P = 0.71; ESRD: r = -0.19, P = 0.65) or arterial oxygen content (AKI: r = -0.17, P = 0.36; ESRD: r = -0.33, P = 0.43). CONCLUSIONS Our data suggest that AKI patients may be more vulnerable than ESRD patients to cerebral hypoperfusion during IHD. Our findings do not support a clear-cut role of rapid changes in blood osmolarity, rheological properties or vasoreactivity of the cerebral circulation to O(2) supply in modulating CBF during hemodialysis.

Colistin Use in Patients With Reduced Kidney Function

Colistin (polymyxin E) is a mainly concentration-dependent bactericidal antimicrobial active against multidrug-resistant Gram-negative bacteria. After being abandoned over the past 30 years due to its neuro- and nephrotoxicity, colistin has been reintroduced recently as a last-resort drug for the treatment of multidrug-resistant Gram-negative bacteria infections in combination with other antimicrobials. Unfortunately, although renal toxicity is a well-known dose-related adverse effect of colistin, relatively few studies are currently available on its peculiar pharmacodynamic/pharmacokinetic properties in clinical settings at high risk for drug accumulation, such as acute or chronic kidney disease. In these specific contexts, the risk for underdosing is also substantial because colistin can be easily removed by dialysis/hemofiltration, especially when the most efficient modalities of renal replacement therapy (RRT) are used in critically ill patients. For this reason, recent recommendations in patients undergoing RRT have shifted toward higher dosing regimens, and therapeutic drug monitoring is advised. This review aims to summarize the main issues related to chemical structure, pharmacodynamics/pharmacokinetics, and renal toxicity of colistin. Moreover, recent data and current recommendations concerning colistin dosing in patients with reduced kidney function, with special regard to those receiving RRT such as dialysis or hemofiltration, are also discussed.

Angiotensin II in Refractory Septic Shock

ABSTRACT Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin–angiotensin–aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

Intradialytic parenteral nutrition in end-stage renal disease: Practical aspects, indications and limits

Protein-energy malnutrition (PEW) is highly prevalent in patients with end-stage renal disease (ESRD) and is associated with a significant increase of the already high mortality and morbidity risk typical of this clinical setting. Since a key mechanism of PEW in ESRD is inadequate nutrient intake, oral nutritional supplements are extensively employed, and have been demonstrated to be highly effective in PEW prevention and treatment. Intradialytic parenteral nutrition (IDPN), i.e. the administration of nutrients through the extracorporeal circuit during hemodialysis, has also been proposed as a modality of nutritional support for patients with ESRD. However, even though metabolic/nutritional status is improved by this nutritional approach, the evidence linking IDPN to decreased hospitalization rate and lower mortality risk is still scant. The aim of the present paper is to review the role of IDPN as a modality of nutritional supplementation for ESRD patients on hemodialysis. To this end, quantitative and qualitative aspects, practical management, the indications, and limits of IDPN are discussed. On the basis of the available evidence, it is suggested that IDPN is a safe and efficacious modality of nutritional support in ESRD, and could represent an adjunctive strategy for patients with reduced spontaneous dietary intake when intensive dietetic counseling and oral supplementation have failed.

Angiotensin II in vasodilatory shock: lights and shadows

Data from the literature show lights and shadows about the use of angiotensin II (Ang II), for instance as an alternative vasopressor in patients with vasodilatory shock that requires high doses of catecholamines. Recently, an international randomized controlled trial (ATHOS-3) [1] has shown that Ang II can induce a significant increase in mean arterial pressure (MAP) if compared to placebo. Moreover, during the first 48 hours from the randomization, doses of the vasopressors (norepinephrine (NE) and vasopressin) were significantly reduced in the Ang II group but not in the placebo group. Interestingly, no difference in adverse effects was remarkable between the two groups. However, some important issues need to be clarified before any definitive conclusion about Ang II in vasodilatory shock. Firstly, we do not know exactly the timing for Ang II initiation: is it better to add Ang II only when NE doses jump to 0.2 μg/kg/min or when NE requirements rapidly increase (e.g., 0.5 μg/kg every hour)? Secondly, Ang II could be administered to specific patients. In previous studies, some patients were extremely sensitive to Ang II infusion (e.g., medication with ACE inhibitors; sartans or betablockers) [2, 3]. Furthermore, cirrhotic patients usually show a reduced angiotensinogen synthesis with secondary low circulating levels of Ang II [4]. In this perspective, could we hypothesize that an early infusion of Ang II has a positive effect on these patients? Thirdly, the safety profile of Ang II has never been tested in patients with vasodilatory shock and concurrent myocardial dysfunction. According to the case of the nonselective nitric oxide synthase inhibitor [5], Ang II could reduce the cardiac output due to its preferential vasoconstrictive action and provide some detrimental effects for those patients with myocardial dysfunction. Finally, Ang II significantly increased the heart rate (HR) in the ATHOS-3 trial. However, Ang II should not have a positive chronotropic effect and the authors did not manage to provide us with a reason for this phenomenon. We can only hypothesize that the increased HR is related to a relative hypovolemia. However, also in this case no clear information about the volemic status was found in the ATHOS-3 trial (e.g., total fluid administration or total fluid balance; cardiac index measurements missed in 56% of cases). In conclusion, Ang II is doubtless a promising vasopressor but some questions still need to be answered before any definitive conclusion in the field.

Cytokine Serum Levels and Septic Myocardial Dysfunction: Is This the Key?

We read with interest the study by Landesberg et al 1 in a recent issue of CHEST (July 2015) and dealing with the correlation between infl ammatory cytokines and myocardial dysfunction in patients with septic shock. In this retrospective analysis, the authors found that biomarkers of cardiac injury, such as high-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide, but not plasma concentrations of cytokines were correlated with echocardiographic evidence of systolic myocardial dysfunction, diastolic myocardial dysfunction, or both or with left ventricular dilation, as suggested by increased end-diastolic left ventricular volume. Th e study off ers new perspectives to clarify the complex pathophysiology of septic myocardial dysfunction, and the authors should be commended for their work.

1013: Renal replacement therapy and mortality during extracorporeal support therapy

Introduction: Acute kidney injury is a common complication in patients treated with extracorporeal membrane oxygenation (ECMO). Continuous renal replacement therapy (CRRT) can help to optimize fluid status and reduce the inflammatory response associated with ECMO. However, published data are derived