Plasma as endothelial rescue in septic shock: A randomized, phase 2a pilot trial.

BACKGROUND: Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer. We evaluated the efficacy and safety aspects of cell-free and pathogen inactivated pooled plasma (OctaplasLG®) as resuscitation in septic shock patients. STUDY DESIGN AND METHODS: This randomized, investigator-initiated phase IIa trial ran at a Danish single center intensive care unit, from 2017 to 2019. Patients were 18 years of age or older with septic shock and randomized to fluid optimization with OctaplasLG® or Ringer-acetate in the first 24 h. The primary endpoints were changes in biomarkers indicative of endothelial activation, damage, and microvascular perfusion from baseline to 24 h. Safety events and mortality were assessed during 90 days. RESULTS: Forty-four patients were randomized, 20 to OctaplasLG versus 24 to Ringer-acetate. The median age was 69, and 55% were men. Median Sequential Organ Failure Assessment score was 13. Baseline differences favoring the Ringer-acetate group were observed. The OctaplasLG® group was resuscitated with 740 mL plasma and the Ringer-acetate group with 841 mL crystalloids. There was no significant change in the microvascular perfusion or five biomarkers except VEGFR1 change, which was higher in patients receiving OctaplasLG® 0.12(SD 0.37) versus Ringer-acetate -0.24 (SD 0.39), with mean difference 0.36 (95% CI, 0.13-0.59, p = .003) in favor of Ringer-acetate. DISCUSSION: This study found that fluid resuscitation with OctaplasLG® in critically ill septic shock patients is feasible. Baseline confounding prevented assessment of the potential effect of OctaplasLG®.

Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.

BACKGROUND: Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).

Facial immersion in cold water enhances cerebral blood velocity during breath-hold exercise in humans.

The diving response is initiated by apnea and facial immersion in cold water and includes, besides bradycardia, peripheral vasoconstriction, while cerebral perfusion may be enhanced. This study evaluated whether facial immersion in 10 degrees C water has an independent influence on cerebral perfusion evaluated as the middle cerebral artery mean flow velocity (MCA V(mean)) during exercise in nine male subjects. At rest, a breath hold of maximum duration increased the arterial carbon dioxide tension (Pa(CO(2))) from 4.2 to 6.7 kPa and MCA V(mean) from 37 to 103 cm/s (mean; approximately 178%; P < 0.001). Similarly, during 100-W exercise, a breath hold increased Pa(CO(2)) from 5.9 to 8.2 kPa (P < 0.001) and MCA V(mean) from 55 to 113 cm/s ( approximately 105%), and facial immersion further increased MCA V(mean) to 122 cm/s ( approximately 88%; both P < 0.001). MCA V(mean) also increased during 180-W exercise (from 47 to 53 cm/s), and this increment became larger with facial immersion (76 cm/s, approximately 62%; P < 0.001), although Pa(CO(2)) did not significantly change. These results indicate that a breath hold diverts blood toward the brain with a >100% increase in MCA V(mean), largely because Pa(CO(2)) increases, but the increase in MCA V(mean) becomes larger when combined with facial immersion in cold water independent of Pa(CO(2)).

Reduced cerebral perfusion on sudden immersion in ice water: a possible cause of drowning.

INTRODUCTION: Near-drowning incidents and drowning deaths after accidental immersion in open waters have been linked to cold shock response. It consists of inspiratory gasps, hyperventilation, tachycardia, and hypertension in the first 2-3 min of cold-water immersion. This study explored the immediate changes in cerebral blood flow velocity (Vmean) during cold-water immersion since cold shock induced hyperventilation may diminish Vmean and lead to syncope and drowning. METHODS: There were 13 male volunteers who were lowered into a 0 degrees C immersion tank for 30 s. Vmean in the middle cerebral artery (MCA) was measured together with ventilatory parameters and heart rate before, during, and after immersion. RESULTS: Within seconds after immersion in ice water, heart rate increased from 74 +/- 16 to 107 +/- 18 bpm (mean +/- SD; p < 0.05). Immersion was associated with a marked elevation in respiratory rate (from 16 +/- 3 to 38 +/- 14 breaths x min(-1)) and tidal volume (883 +/- 360 to 2292 +/- 689 ml). The end-tidal carbon dioxide tension decreased from 38 +/- 4 to 26 +/- 5 mmHg and MCA Vmean dropped by 43 +/- 8%. Signs of imminent syncope (drowsiness, blurred vision, loss of responsiveness) were shown by two subjects (MCA Vmean dropped 62% and 68%, respectively). DISCUSSION: Following ice-water immersion, hyperventilation induced a marked reduction in MCA Vmean to a level which has been associated with disorientation and loss of consciousness.

Coagulation competence and fluid recruitment after moderate blood loss in young men.

The coagulation system is activated by a reduction of the central blood volume during orthostatic stress and lower body negative pressure suggesting that also a blood loss enhances coagulation. During bleeding, however, the central blood volume is supported by fluid recruitment to the circulation and redistribution of the blood volume. In eight supine male volunteers (24 ± 3 years, blood volume of 6.9 ± 0.7 l; mean ± SD), 2 × 450 ml blood was withdrawn over ∼ 30 min while cardiovascular variables were monitored. Coagulation was evaluated by thrombelastography, and fluid recruitment was estimated by red blood cell count. Withdrawing 900 ml blood increased heart rate (62 ± 7 to 69 ± 13 bpm, P < 0.05; mean ± SD) and reduced stroke volume (113 ± 12 to 96 ± 14 ml, P < 0.05) leaving cardiac output, mean arterial pressure, and total peripheral resistance unchanged and, furthermore, reduced red blood cell count (4.80 ± 0.33 to 4.64 ± 0.37 × 10(12) cells l(-1), P < 0.05) indicating that 218 ± 173 ml fluid was recruited to the circulation. Withdrawing 450 ml blood reduced the time until initial fibrin formation (R: 6.5 ± 0.9 to 5.1 ± 1.0 min, P < 0.01), whereas the rate of clot formation increased after withdrawal of 900 ml blood (α-Angle: 66 ± 4 to 70 ± 3 deg, P < 0.01). Clot strength (maximal amplitude: 57 ± 4 mm), clot lysis 30 min after maximal amplitude (LY30: 0.8% [0-3.5%] (median [range])), and platelet count (218 ± 25 × 10(9) l(-1)) were unaffected. For supine males, ∼ 25% of a moderate blood loss is compensated by fluid recruitment to the circulation, which may explain the minor cardiovascular response. Yet, a blood loss of 450 ml accelerates coagulation, and this is further accentuated when blood loss is 900 ml.

Cardiovascular consequence of reclining vs. sitting beach-chair body position for induction of anesthesia.

The sitting beach-chair position is regularly used for shoulder surgery and anesthesia may be induced in that position. We tested the hypothesis that the cardiovascular challenge induced by induction of anesthesia is attenuated if the patient is placed in a reclining beach-chair position. Anesthesia was induced with propofol in the sitting beach-chair (n = 15) or with the beach-chair tilted backwards to a reclining beach-chair position (n = 15). The last group was stepwise tilted to the sitting beach-chair position prior to surgery. Hypotension was treated with ephedrine. Continuous hemodynamic variables were recorded by photoplethysmography and frontal cerebral oxygenation (ScO2) by near infrared spectroscopy. Significant differences were only observed immediately after the induction when patients induced in a reclining beach-chair position had higher mean arterial pressure (MAP) (35 ± 12 vs. 45 ± 15 % reduction from baseline, p = 0.04) and ScO2 (7 ± 6 vs. 1 ± 8% increase from baseline, p = 0.02) and received less ephedrine (mean: 4 vs. 13 mg, p = 0.048). The higher blood pressure and lower need of vasopressor following induction of anesthesia in the reclining compared to the sitting beach-chair position indicate more stable hemodynamics with the clinical implication that anesthesia should not be induced with the patient in the sitting position.

Effect of head rotation on cerebral blood velocity in the prone position.

Background. The prone position is applied to facilitate surgery of the back and to improve oxygenation in the respirator-treated patient. In particular, with positive pressure ventilation the prone position reduces venous return to the heart and in turn cardiac output (CO) with consequences for cerebral blood flow. We tested in healthy subjects the hypothesis that rotating the head in the prone position reduces cerebral blood flow. Methods. Mean arterial blood pressure (MAP), stroke volume (SV), and CO were determined, together with the middle cerebral artery mean blood velocity (MCA V(mean)) and jugular vein diameters bilaterally in 22 healthy subjects in the prone position with the head centered, respectively, rotated sideways, with and without positive pressure breathing (10 cmH(2)O). Results. The prone position reduced SV (by 5.4 ± 1.5%; P < 0.05) and CO (by 2.3 ± 1.9 %), and slightly increased MAP (from 78 ± 3 to 80 ± 2 mmHg) as well as bilateral jugular vein diameters, leaving MCA V(mean) unchanged. Positive pressure breathing in the prone position increased MAP (by 3.6 ± 0.8 mmHg) but further reduced SV and CO (by 9.3 ± 1.3 % and 7.2 ± 2.4 % below baseline) while MCA V(mean) was maintained. The head-rotated prone position with positive pressure breathing augmented MAP further (87 ± 2 mmHg) but not CO, narrowed both jugular vein diameters, and reduced MCA V(mean) (by 8.6 ± 3.2 %). Conclusion. During positive pressure breathing the prone position with sideways rotated head reduces MCA V(mean) ~10% in spite of an elevated MAP. Prone positioning with rotated head affects both CBF and cerebrovenous drainage indicating that optimal brain perfusion requires head centering.

Cerebral autoregulation dynamics in endurance-trained individuals.

Aerobic fitness may be associated with reduced orthostatic tolerance. To investigate whether trained individuals have less effective regulation of cerebral vascular resistance, we studied the middle cerebral artery (MCA) mean blood velocity (V(mean)) response to a sudden drop in mean arterial pressure (MAP) after 2.5 min of leg ischemia in endurance athletes and untrained subjects (maximal O(2) uptake: 69 ± 7 vs. 42 ± 5 ml O(2)·min(-1)·kg(-1); n = 9 for both, means ± SE). After cuff release when seated, endurance athletes had larger drops in MAP (94 ± 6 to 62 ± 5 mmHg, -39%, vs. 99 ± 5 to 73 ± 4 mmHg, -26%) and MCA V(mean) (53 ± 3 to 37 ± 2 cm/s, -30%, vs. 58 ± 3 to 43 ± 2 cm/s, -25%). The athletes also had a slower recovery to baseline of both MAP (25 ± 2 vs. 16 ± 1 s, P < 0.01) and MCA V(mean) (15 ± 1 vs. 11 ± 1 s, P < 0.05). The onset of autoregulation, determined by the time point of increase in the cerebrovascular conductance index (CVCi = MCA V(mean)/MAP) appeared later in the athletes (3.9 ± 0.4 vs. 2.7 ± 0.4s, P = 0.01). Spectral analysis revealed a normal MAP-to-MCA V(mean) phase in both groups but ~40% higher normalized MAP to MCA V(mean) low-frequency transfer function gain in the trained subjects. No significant differences were detected in the rates of recovery of MAP and MCA V(mean) and the rate of CVCi regulation (18 ± 4 vs. 24 ± 7%/s, P = 0.2). In highly trained endurance athletes, a drop in blood pressure after the release of resting leg ischemia was more pronounced than in untrained subjects and was associated with parallel changes in indexes of cerebral blood flow. Once initiated, the autoregulatory response was similar between the groups. A delayed onset of autoregulation with a larger normalized transfer gain conforms with a less effective dampening of MAP oscillations, indicating that athletes may be more prone to instances of symptomatic cerebral hypoperfusion when MAP declines.

Activated protein synthesis and suppressed protein breakdown signaling in skeletal muscle of critically ill patients.

BACKGROUND: Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3ß (GSK3ß) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3ß, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated. CONCLUSIONS/SIGNIFICANCE: We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.