Management of spontaneous intracranial hypotension - Transorbital ultrasound as discriminator.

OBJECTIVE Spontaneous intracranial hypotension (SIH) is most commonly caused by cerebrospinal fluid (CSF) leakage. Therefore, we hypothesised that patients with orthostatic headache (OH) would show decreased optic nerve sheath diameter (ONSD) during changes from supine to upright position. METHODS Transorbital B-mode ultrasound was performed employing a high-frequency transducer for ONSD measurements in the supine and upright positions. Absolute values and changes of ONSD from supine to upright were assessed. Ultrasound was performed in 39 SIH patients, 18 with OH and 21 without OH, and in 39 age-matched control subjects. The control group comprised 20 patients admitted for back surgery without headache or any orthostatic symptoms, and 19 healthy controls. RESULTS In supine position, mean ONSD (±SD) was similar in patients with (5.38±0.91 mm) or without OH (5.48±0.89 mm; p=0.921). However, in upright position, mean ONSD was different between patients with (4.84±0.99 mm) and without OH (5.53±0.99 mm; p=0.044). Furthermore, the change in ONSD from supine to upright position was significantly greater in SIH patients with OH (-0.53±0.34 mm) than in SIH patients without OH (0.05±0.41 mm; p≤0.001) or in control subjects (0.01±0.38 mm; p≤0.001; area under the curve: 0.874 in receiver operating characteristics analysis). CONCLUSIONS Symptomatic patients with SIH showed a significant decrease of ONSD, as assessed by ultrasound, when changing from the supine to the upright position. Ultrasound assessment of the ONSD in two positions may be a novel, non-invasive tool for the diagnosis and follow-up of SIH and for elucidating the pathophysiology of SIH.

Hypotension and hypovolemia during hemodialysis: is the usual suspect innocent?

Hypotension during intermittent hemodialysis is common, and has been attributed to acute volume shifts, shifts in osmolarity, electrolyte imbalance, temperature changes, altered vasoregulation, and sheer hypovolemia. Although hypovolemia may intuitively seem a likely cause for hypotension in intensive care patients, its role in the pathogenesis of intradialytic hypotension may be overestimated.

Hypotension and inflammatory cytokine gene expression triggered by factor Xa–nitric oxide signaling

The signaling pathway initiated by factor Xa on vascular endothelial cells was investigated. Factor Xa stimulated a 5- to 10-fold increased release of nitric oxide (NO) in a dose-dependent reaction (0.1–2.5 μg/ml) unaffected by the thrombin inhibitor hirudin but abolished by active site inhibitors, tick anticoagulant peptide, or Glu-Gly-Arg-chloromethyl ketone. In contrast, the homologous clotting protease factor IXa or another endothelial cell ligand, fibrinogen, was ineffective. A factor Xa inter-epidermal growth factor synthetic peptide L83FTRKL88(G) blocking ligand binding to effector cell protease receptor-1 inhibited NO release by factor Xa in a dose-dependent manner, whereas a control scrambled peptide KFTGRLL was ineffective. Catalytically active factor Xa induced hypotension in rats and vasorelaxation in the isolated rat mesentery, which was blocked by the NO synthase inhibitor l-NG-nitroarginine methyl ester (l-NAME) but not by d-NAME. Factor Xa/NO signaling also produced a dose-dependent endothelial cell release of interleukin 6 (range 0.55–3.1 ng/ml) in a reaction inhibited by l-NAME and by the inter-epidermal growth factor peptide Leu83–Leu88 but unaffected by hirudin. Maximal induction of interleukin 6 mRNA required a brief, 30-min stimulation with factor Xa, unaffected by subsequent addition of tissue factor pathway inhibitor. These data suggest that factor Xa-induced NO release modulates endothelial cell-dependent vasorelaxation and cytokine gene expression. This pathway requiring factor Xa binding to effector cell protease receptor-1 and a secondary step of ligand-dependent proteolysis may preserve an anti-thrombotic phenotype of endothelium but also trigger acute phase responses during activation of coagulation in vivo.

Arrest of endotoxin-induced hypotension by transforming growth factor beta1.

Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the infecting organism trigger a cascade of events leading to hypotension, to multiple organ system failure, and frequently to death. Beyond supportive care, no effective therapy is available for the treatment of septic shock. Nitric oxide (NO) is a potent vasodilator generated late in the sepsis pathway leading to hypotension; therefore, NO represents a potential target for therapy. We have previously demonstrated that transforming growth factor (TGF) beta1 inhibits inducible NO synthase (iNOS) mRNA and NO production in vascular smooth muscle cells after its induction by cytokines critical in the sepsis cascade. Thus, we hypothesized that TGF-beta1 may inhibit iNOS gene expression in vivo and be beneficial in the treatment of septic shock. In a conscious rat model of septic shock produced by Salmonella typhosa lipopolysaccharide (LPS), TGF-beta1 markedly reduced iNOS mRNA and protein levels in several organs. In contrast, TGF-beta1 did not decrease endothelium-derived constitutive NOS mRNA in organs of rats receiving LPS. We also performed studies in anesthetized rats to evaluate the effect of TGF-beta1 on the hemodynamic compromise of septic shock; after an initial 25% decrease in mean arterial pressure, TGF-beta1 arrested LPS-induced hypotension and decreased mortality. A decrease in iNOS mRNA and protein levels in vascular smooth muscle cells was demonstrated by in situ hybridization and NADPH diaphorase staining in rats treated with TGF-beta1. Thus these studies suggest that TGF-beta1 inhibits iNOS in vivo and that TGF-beta1 may be of future benefit in the therapy of septic shock.

Asymptomatic intradialytic hypotension: the need for pre-emptive intervention

Intradialytic hypotension (IDH) remains the most common severe side effect of hemodialysis despite numerous technological advancements. Recent evidence emphasises the significance of asymptomatic hypotensive episodes, as well as the hypoperfusive consequences of both relative blood pressure drops and repetitive, symptomatic events. This article reviews the physiological importance of rapid blood pressure decrease during hemodialysis, and highlights the pathological consequences of repeated asymptomatic and symptomatic hypoperfusive episodes. In proposing a view concerned with asymptomatic IDH, a practicalpre-emptive intervention is offered to improve the long-term outcomes of patients on hemodialysis. Ongoing monitoring of individual patient's mean arterial pressure (MAP) throughout the dialysis treatment can facilitate the identification of an asymptomatic hypotensive episode. A brief pause in ultrafiltration enables vascular refill and subsequent increase in MAP, allowing resumption of safe fluid removal. Such enhanced assessment results in a reduction off patient risk, allowing safe and optimal fluid removal.

Physiological and symptomatic responses to cycling and walking in intermittent claudication

To shed light on the potential efficacy of cycling as a testing modality in the treatment of intermittent claudication (IC), this study compared physiological and symptomatic responses to graded walking and cycling tests in claudicants. Sixteen subjects with peripheral arterial disease (resting ankle: brachial index (ABI) < 0.9) and IC completed a maximal graded treadmill walking (T) and cycle (C) test after three familiarization tests on each mode. During each test, symptoms, oxygen uptake (VO2), minute ventilation (VE), respiratory exchange ratio (RER) and heart rate (HR) were measured, and for 10 min after each test the brachial and ankle systolic pressures were recorded. All but one subject experienced calf pain as the primary limiting symptom during T; whereas the symptoms were more varied during C and included thigh pain, calf pain and dyspnoea. Although maximal exercise time was significantly longer on C than T (690 +/- 67 vs. 495 +/- 57 s), peak VO2, peak VE and peak heart rate during C and T were not different; whereas peak RER was higher during C. These responses during C and T were also positively correlated (P < 0.05) with each other, with the exception of RER. The postexercise systolic pressures were also not different between C and T. However, the peak decline in ankle pressures from resting values after C and T were not correlated with each other. These data demonstrate that cycling and walking induce a similar level of metabolic and cardiovascular strain, but that the primary limiting symptoms and haemodynamic response in an individual's extremity, measured after exercise, can differ substantially between these two modes.

Influence of preexercise muscle glycogen content on transcriptional activity of metabolic and myogenic genes in well-trained humans

To determine whether pre-exercise muscle glycogen content influences the transcription of several early-response genes involved in the regulation of muscle growth, seven male strength-trained subjects performed one-legged cycling exercise to exhaustion to lower muscle glycogen levels (Low) in one leg compared with the leg with normal muscle glycogen (Norm) and then the following day completed a unilateral bout of resistance training (RT). Muscle biopsies from both legs were taken at rest, immediately after RT, and after 3 h of recovery. Resting glycogen content was higher in the control leg (Norm leg) than in the Low leg (435 ± 87 vs. 193 ± 29 mmol/kg dry wt; P < 0.01). RT decreased glycogen content in both legs (P < 0.05), but postexercise values remained significantly higher in the Norm than the Low leg (312 ± 129 vs. 102 ± 34 mmol/kg dry wt; P < 0.01). GLUT4 (3-fold; P < 0.01) and glycogenin mRNA abundance (2.5-fold; not significant) were elevated at rest in the Norm leg, but such differences were abolished after exercise. Preexercise mRNA abundance of atrogenes was also higher in the Norm compared with the Low leg [atrogin: ?14-fold, P < 0.01; RING (really interesting novel gene) finger: ?3-fold, P < 0.05] but decreased for atrogin in Norm following RT (P < 0.05). There were no differences in the mRNA abundance of myogenic regulatory factors and IGF-I in the Norm compared with the Low leg. Our results demonstrate that 1) low muscle glycogen content has variable effects on the basal transcription of select metabolic and myogenic genes at rest, and 2) any differences in basal transcription are completely abolished after a single bout of heavy resistance training. We conclude that commencing resistance exercise with low muscle glycogen does not enhance the activity of genes implicated in promoting hypertrophy.

Early signaling responses to divergent exercise stimuli in skeletal muscle from well-trained humans

Skeletal muscle from strength- and endurance-trained individuals represents diverse adaptive states. In this regard, AMPK-PGC-1α signaling mediates several adaptations to endurance training, while up-regulation of the Akt-TSC2-mTOR pathway may underlie increased protein synthesis after resistance exercise. We determined the effect of prior training history on signaling responses in seven strength-trained and six endurance-trained males who undertook 1 h cycling at 70% VO2peak or eight sets of five maximal repetitions of isokinetic leg extensions. Muscle biopsies were taken at rest, immediately and 3 h postexercise. AMPK phosphorylation increased after cycling in strength-trained (54%; P<0.05) but not endurance-trained subjects. Conversely, AMPK was elevated after resistance exercise in endurance- (114%; P<0.05), but not strengthtrained subjects. Akt phosphorylation increased in endurance- (50%; P<0.05), but not strengthtrained subjects after cycling but was unchanged in either group after resistance exercise. TSC2 phosphorylation was decreased (47%; P<0.05) in endurance-trained subjects following resistance exercise, but cycling had little effect on the phosphorylation state of this protein in either group. p70S6K phosphorylation increased in endurance- (118%; P<0.05), but not strength-trained subjects after resistance exercise, but was similar to rest in both groups after cycling. Similarly, phosphorylation of S6 protein, a substrate for p70 S6K, was increased immediately following resistance exercise in endurance- (129%; P<0.05), but not strength-trained subjects. In conclusion, a degree of “response plasticity” is conserved at opposite ends of the endurancehypertrophic adaptation continuum. Moreover, prior training attenuates the exercise specific signaling responses involved in single mode adaptations to training.

Renal and genitourinary emergencies

Genitourinary (GU) problems are a common complaint in the community and to the emergency department (ED). Urinary tract infections (UTIs) are the second most common bacterial disease. UTIs rank as the sixteenth most frequently reported problem to general practitioners in Australia1 and between 10% and 20% of women will experience at least one UTI in their lifetime. Over 1,000,000 Australians are currently suffering with nephrolithiasis (renal calculi) and it is hy-pothesised that Australia’s hot, dry climate causes more stone formation than many other coun-tries in the world. Acute kidney injury (AKI) is a common complication of any trauma. Hypovol-aemia results in severe hypotension and this precipitates the development of acute tubular necrosis and subsequent AKI. The incidence of chronic kidney disease (CKD) is rising across the world. CKD is classified into five stages with those in stage 5 being classified as being in end stage kidney disease (ESKD). It is estimated that there are over 1.5 million people in Australia with CKD and there were over 16,000 Australians and over 2900 individuals in New Zealand with ESKD.2 Indigenous populations from both countries (Aboriginals, Torres Strait Islanders, Maoris, and Pacific Islanders) are over-represented in the number of people with all stages of CKD in both countries. Patients with compromised renal function often require the assistance of paramedics and will arrive at the ED with life-threatening fluid and electrolyte imbalances. Spe-cific GU emergencies discussed in this chapter are acute renal failure, rhabdomyolysis, chronic kidney disease, UTIs, acute urinary retention, urinary calculi, testicular torsion, epididymitis, and priapism. Refer to Chapter 31 for discussion of sexually transmitted infections (STIs) in women and to Chapter X for discussion of genitourinary trauma.

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

Purpose: To measure renal adenosine triphosphate (ATP) (bioenergetics) during hypotensive sepsis with or without angiotensin II (Ang II) infusion. Methods: In anaesthetised sheep implanted with a renal artery flow probe and a magnetic resonance coil around one kidney, we induced hypotensive sepsis with intravenous Escherichia coli injection. We measured mean arterial pressure (MAP), heart rate, renal blood flow RBF and renal ATP levels using magnetic resonance spectroscopy. After 2 h of sepsis, we randomly assigned sheep to receive an infusion of Ang II or vehicle intravenously and studied the effect of treatment on the same variables. Results: After E. coli administration, the experimental animals developed hypotensive sepsis (MAP from 92 ± 9 at baseline to 58 ± 4 mmHg at 4 h). Initially, RBF increased, then, after 4 h, it decreased below control levels (from 175 ± 28 at baseline to 138 ± 27 mL/min). Despite decreased RBF and hypotension, renal ATP was unchanged (total ATP to inorganic phosphate ratio from 0.69 ± 0.02 to 0.70 ± 0.02). Ang II infusion restored MAP but caused significant renal vasoconstriction. However, it induced no changes in renal ATP (total ATP to inorganic phosphate ratio from 0.79 ± 0.03 to 0.80 ± 0.02). Conclusions:During early hypotensive experimental Gram-negative sepsis, there was no evidence of renal bioenergetic failure despite decreased RBF. In this setting, the addition of a powerful renal vasoconstrictor does not lead to deterioration in renal bioenergetics.

Effects of bovine colostrum supplementation on immune variables of highly-trained cyclists

The aim of this study was to investigate the influence of low-dose bovine colostrum protein concentrate (CPC) supplementation on selected immune variables in cyclists. Twenty-nine highly trained male road cyclists completed an initial 40-km time trial (TT(40)) and were then randomly assigned to either a supplement (n = 14, 10 g bovine CPC/day) or placebo group (n = 15, 10 g whey protein concentrate/day). After 5 wk of supplementation, the cyclists completed a second TT(40). They then completed 5 consecutive days of high-intensity training (HIT) that included a TT(40), followed by a final TT(40) in the following week. Venous blood and saliva samples were collected immediately before and after each TT(40), and upper respiratory illness symptoms were recorded over the experimental period. Compared with the placebo group, bovine CPC supplementation significantly increased preexercise serum soluble TNF receptor 1 during the HIT period (bovine CPC = 882 +/- 233 pg/ml, placebo = 468 +/- 139 pg/ml; P = 0.039). Supplementation also suppressed the postexercise decrease in cytotoxic/suppressor T cells during the HIT period (bovine CPC = -1.0 +/- 2.7%, placebo = -9.2 +/- 2.8%; P = 0.017) and during the following week (bovine CPC = 1.4 +/- 2.9%, placebo = -8.2 +/- 2.8%; P = 0.004). Bovine CPC supplementation prevented a postexercise decrease in serum IgG(2) concentration at the end of the HIT period (bovine CPC = 4.8 +/- 6.8%, P = 0.88; placebo = -9.7 +/- 6.9%, P = 0.013). There was a trend toward reduced incidence of upper respiratory illness symptoms in the bovine CPC group (P = 0.055). In summary, low-dose bovine CPC supplementation modulates immune parameters during normal training and after an acute period of intense exercise, which may have contributed to the trend toward reduced upper respiratory illness in the bovine CPC group.

Changes in neutrophil surface receptor expression, degranulation, and respiratory burst activity after moderate- and high-intensity exercise

Intense exercise stimulates the systemic release of a variety of factors that alter neutrophil surface receptor expression and functional activity. These alterations may influence resistance to infection after intense exercise. The aim of this study was to examine the influence of exercise intensity on neutrophil receptor expression, degranulation (measured by plasma and intracellular myeloperoxidase concentrations), and respiratory burst activity. Ten well-trained male runners ran on a treadmill for 60 min at 60% [moderate-intensity exercise (MI)] and 85% maximal oxygen consumption [high-intensity exercise (HI)]. Blood was drawn immediately before and after exercise and at 1 h postexercise. Immediately after HI, the expression of the neutrophil receptor CD16 was significantly below preexercise values (P < 0.01), whereas MI significantly reduced CD35 expression below preexercise values (P < 0.05). One hour after exercise at both intensities, there was a significant decline in CD11b expression (P < 0.05) and a further decrease in CD16 expression compared with preexercise values (P < 0.01). CD16 expression was lower 1 h after HI than 1 h after MI (P < 0.01). Immediately after HI, intracellular myeloperoxidase concentration was less than preexercise values (P < 0.01), whereas plasma myeloperoxidase concentration was greater (P < 0.01), indicating that HI stimulated neutrophil degranulation. Plasma myeloperoxidase concentration was higher immediately after HI than after MI (P < 0.01). Neutrophil respiratory burst activity increased after HI (P < 0.01). In summary, both MI and HI reduced neutrophil surface receptor expression. Although CD16 expression was reduced to a greater extent after HI, this reduction did not impair neutrophil degranulation and respiratory burst activity.

Vitamin C : effects of exercise and requirements with training

Ascorbic acid or vitamin C is involved in a number of biochemical pathways that are important to exercise metabolism and the health of exercising individuals. This review reports the results of studies investigating the requirement for vitamin C with exercise on the basis of dietary vitamin C intakes, the response to supplementation and alterations in plasma, serum, and leukocyte ascorbic acid concentration following both acute exercise and regular training. The possible physiological significance of changes in ascorbic acid with exercise is also addressed. Exercise generally causes a transient increase in circulating ascorbic acid in the hours following exercise, but a decline below pre-exercise levels occurs in the days after prolonged exercise. These changes could be associated with increased exercise-induced oxidative stress. On the basis of alterations in the concentration of ascorbic acid within the blood, it remains unclear if regular exercise increases the metabolism of vitamin C. However, the similar dietary intakes and responses to supplementation between athletes and nonathletes suggest that regular exercise does not increase the requirement for vitamin C in athletes. Two novel hypotheses are put forward to explain recent findings of attenuated levels of cortisol postexercise following supplementation with high doses of vitamin C.