The Effect of Propofol and Dexmedetomidine Sedation on Norepinephrine Requirements in Septic Shock Patients: A Crossover Trial.

OBJECTIVES: Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. α-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the α-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock. DESIGN: Prospective open-label crossover study. SETTINGS: University hospital, ICU. PATIENTS: Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4. INTERVENTIONS: An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period. MEASUREMENTS AND MAIN RESULTS: Norepinephrine requirements decreased from 0.69 ± 0.72 µg/kg/min before dexmedetomidine to 0.30 ± 0.25 µg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 µg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 µg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 µg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07). CONCLUSIONS: For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.

Fluid resuscitation in patients with traumatic brain injury: what is a SAFE approach?

PURPOSE OF REVIEW: In patients with traumatic brain injury (TBI), dysfunction of the neurovascular unit ('blood-brain barrier') is a common finding, resulting in maldistribution of water and osmoles within the brain. The purpose of the present article is to review the underlying physiology of osmolality and fluid therapy in TBI. RECENT FINDINGS: The findings of the 'Saline versus Albumin Fluid Evaluation' study suggest that infusion of colloidal solutions is associated with adverse outcomes as compared with sole crystalloid infusion in patients suffering from TBI. Comparison of calculated osmolarity and measured in-vitro osmolality suggests that human albumin solutions, Hartmann's solution, and, to a lesser extent, gelatine preparations are hypo-osmolar, and may, therefore, increase brain volume and intracranial pressure. SUMMARY: In the context of the published literature on this topic, it appears that the osmolality of an infusion solution rather than the colloid osmotic pressure per se represents the key determinant in the pathogenesis of cerebral edema formation.

Effects of balanced crystalloid vs. 0.9% saline-based vs. balanced 6% tetrastarch infusion on renal function and tubular integrity in ovine endotoxemic shock.

OBJECTIVE: Conflicting data exist on the renal effects of hydroxyethyl starch preparations. The aim of the present study was to evaluate the impact of balanced crystalloids, as well as 0.9% saline-based and balanced 6% tetrastarch solutions, on renal function and ultrastructural morphologic correlates of acute kidney injury in an established model of ovine endotoxemic shock. DESIGN: Randomized, controlled, experimental study. SETTING: Animal research facility of a university hospital. SUBJECTS: A total of 31 awake instrumented sheep. INTERVENTIONS: The animals were subjected to continuous endotoxin infusion (Salmonella typhosa) at incremental doses until the mean arterial pressure was <65 mm Hg and arterial lactate was ≥ 2 mmol·L⁻¹ or (if arterial hypotension was absent) arterial lactate was ≥ 4 mmol·L⁻¹. The subjects were then randomized to receive no fluid resuscitation (control group, n = 5) or blinded infusion of a balanced crystalloid (n = 9), 0.9% saline-based (n = 8), or balanced 6% hydroxyethyl starch 130/0.4 (n = 9) up to a maximum dose of 50 mL·kg⁻¹, followed by open-label infusion of balanced crystalloid. Animals surviving the 12-hr intervention period were deeply anesthetized and killed. Kidney samples were taken immediately for transmission electron microscopic analyses. Additional specific experiments were performed to take kidney samples ex vivo. MEASUREMENTS AND MAIN RESULTS: Endotoxemia was associated with arterial hypotension and capillary leakage. Fluid resuscitation established a hypotensive-hyperdynamic circulation in all resuscitated animals without significant hemodynamic differences among groups. Plasma creatinine and urea concentrations were higher in both hydroxyethyl starch groups as compared to the crystalloid group (creatinine, 1.2 ± 0.1 and 1.4 ± 0.3 vs. 0.8 ± 0.1 mg·dL⁻¹; urea, 21 ± 1 and 21 ± 2 vs. 17 ± 2 mg·dL⁻¹; p < .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids at 8 hrs). In contrast, kidney function, as measured by creatinine clearance and cumulative creatinine excretion, was similar between the colloid and crystalloid treatment groups (creatinine clearance at 8 hrs, 122 ± 18 and 108 ± 31 vs. 107 ± 13 mL·min⁻¹·m⁻²; creatinine excretion per hour alive, 283 ± 29 and 264 ± 19 vs. 291 ± 24 mg·hr⁻¹; p > .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids), whereas kidney function deteriorated markedly in control animals. The electron microscopic tubular injury score was lower in hydroxyethyl starch-treated animals as compared to the crystalloid group. Vacuolar tubular cell alterations were present in all groups. The percentage of intact microvilli brush borders was significantly higher in sheep treated with either hydroxyethyl starch solution as compared to the other groups. CONCLUSIONS: The present study provides evidence that renal function, as measured by creatinine clearance and cumulative creatinine excretion as well as ultrastructural tubular integrity, is preserved with the use of 6% tetrastarch solutions despite increases in plasma levels of renal retention variables in ovine endotoxemic shock.

Effects of two different dosing regimens of terlipressin on organ functions in ovine endotoxemia.

OBJECTIVE AND DESIGN: To test the hypothesis that a continuous infusion of the vasopressin analog terlipressin is associated with less organ dysfunction as compared to intermittent bolus infusion in an ovine sepsis model. SUBJECTS: Twenty-seven adult female sheep. TREATMENT: All sheep were subjected to a Salmonella typhosa endotoxin infusion (10 ng/kg/min). After 16 h of endotoxemia, the surviving animals (n = 24) were randomized to (1) an untreated control group, (2) a continuous terlipressin group (2 mg/24 h), or (3) a terlipressin bolus group (1 mg/6 h). METHODS: Hemodynamic variables were measured and blood was withdrawn at specific time points for the assessment of organ functions. RESULTS: Continuous terlipressin infusion was associated with improved surrogate parameters of myocardial, renal, and hepatic function as compared with terlipressin bolus infusion. Reduced vascular hyperpermeability was evidenced by an attenuated decrease in plasma protein concentrations in sheep treated with continuous terlipressin infusion as compared to bolus injection or no treatment. CONCLUSIONS: Continuous infusion of low-dose terlipressin preserved several surrogate parameters of organ function better than intermittent bolus injections in sheep with systemic inflammation.

Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study.

INTRODUCTION: V(2)-receptor (V(2)R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V(2)R-antagonist (Propionyl(1)-D-Tyr(Et)(2)-Val(4)-Abu(6)-Arg(8,9))-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V(1a)R/V(2)R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock. METHODS: After the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V(2)R-antagonist (1 µg/kg per hour), AVP (0.05 µg/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 µg/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary. RESULTS: Compared to AVP- and placebo-treated animals, the selective V(2)R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V(2)R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V(2)R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V(2)R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V(2)R-antagonist group. In addition, the selective V(2)R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025). CONCLUSIONS: Selective V(2)R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.

Comparison of first-line and second-line terlipressin versus sole norepinephrine in fulminant ovine septic shock.

The Surviving Sepsis Guidelines suggest the use of vasopressin in case of catecholamine-refractory septic shock. Terlipressin (TP) as a V1-selective AVP analogue is a potential alternative, though data regarding the first-line administration in septic shock are scarce. The present study explored and compared the effects of first-line vs. second-line infusion of TP or sole norepinephrine regarding organ function, fluid and norepinephrine requirements and survival in fulminant ovine septic shock. Peritoneal sepsis was induced in 23 ewes after laparotomy and faecal withdrawal from the caecum. After onset of shock, causal and supportive sepsis therapy (antibiotics, peritoneal lavage, fluids and open-label norepinephrine) was performed in all animals. Concurrently, animals were randomized to receive 0.9% sodium chloride (control group) or TP (2 µg∙kg-1∙h-1, first-line group) after shock onset. In the second-line TP group, TP (2 µg∙kg-1∙h-1) was started once norepinephrine requirements exceeded 0.5 µg∙kg-1∙min-1. No significant differences were found between groups regarding survival, haemodynamics as well as fluid- and catecholamine-requirements. Kidney function and electron microscopic kidney injury were comparable between groups. In the present model of fulminant ovine septic shock, first-line TP infusion had no significant effect on fluid and norepinephrine requirements or organ dysfunction as compared to second-line TP infusion or placebo.

Update on volume therapy in obstetrics.

Symptomatic hypotension (maternal nausea, vomiting, dizziness and dyspnoea) during spinal anaesthesia for caesarean delivery remains a prevalent clinical problem. Severe and sustained hypotension can lead to impairment of uteroplacental perfusion, foetal hypoxia, acidosis, neonatal depression and further adverse maternal outcomes of unconsciousness, pulmonary aspiration, apnoea and cardiac arrest. Mechanical methods aimed at countering the effects of aortocaval compression do not reliably prevent maternal hypotension. Intravenous crystalloid preloading (given prior to administration of spinal anaesthesia) has poor efficacy, and focus has changed towards decreased use of crystalloid preload and ephedrine, to increased use of coload (given at the time of spinal administration) with colloids or crystalloids, and early use of phenylephrine. The recent multicentre, randomised, double-blinded CAESAR trial demonstrated the efficacy of a mixed 500 ml 6% hydroxyethyl starch (HES) 130/0.4 + 500 ml Ringer's lactate (RL) preload in significantly reducing hypotension, compared to a 1-l RL preload, without adverse effects on coagulation and neonatal outcomes in healthy parturients undergoing caesarean delivery under spinal anaesthesia.

Translational research in sepsis - an ultimate challenge?

In the era of evidence-based medicine, large, randomized, controlled, multicenter studies represent the "summit of evidence". In contrast to specialties like cardiology, the majority of randomized, controlled trials in critical care medicine, however, have failed to demonstrate a survival benefit; notably, despite encouraging results from experimental and phase-II clinical studies. The difficulty in translating our theoretical knowledge into successful multicenter randomized, controlled trials and subsequent treatment recommendations may represent one reason, why the mortality of septic shock still averages between 40-60%, although our knowledge about the underlying pathophysiology has considerably increased and international guidelines have widely been implemented. The present article elucidates some of the difficulties in translating research from bench to bedside.