R. A. Little

Shock index: a re-evaluation in acute circulatory failure

STUDY OBJECTIVE To evaluate the relationship between the shock index SI (ratio of heart rate to systolic arterial pressure) and cardiac function and oxygen transport in an experimental model of hemorrhage and clinical septic shock. METHODS AND RESULTS This study was conducted in a hypovolemic circulatory failure model; 40% hemorrhage in the anesthetized pig and normovolemic hyperdynamic septic patients in the intensive care unit (ICU). Hemodynamic and oxygen transport variables were measured and their relationships to SI was examined. SI was inversely related to blood loss, cardiac index (CI), stroke volume (SV), mean arterial pressure (MAP) and left ventricular stroke work (LVSW) (r = -0.73, -0.75, -0.89 and -0.75, respectively P less than 0.01) following hemorrhage in the anesthetized pig. Oxygen transport variables, i.e. oxygen delivery (DO2) and mixed venous oxygen saturation (SvO2P) (r = -0.68 and -0.74, respectively, P less than 0.01) were also inversely related to the SI. Oxygen consumption (VO2) increased initially with increasing SI and fell when SI was greater than 3.0. In clinical septic shock and following blood volume expansion, the SI was not correlated to CI, SVI, MAP or systemic vascular resistance (SVR) (r = -0.01, -0.47, -0.34 and -0.14, respectively, P-value NS) but was inversely related to LVSWI (r = -0.68, P less than 0.01). There were no relationships between the SI and oxygen transport variables (DO2, SvO2) (r = -0.02 and -0.17, P-value NS) in septic shock. CONCLUSION SI provides a non-invasive means to monitor deterioration or recovery of LVSW during acute hypovolemic and normovolemic circulatory failure and its therapy. SI may be of limited value in the assessment of systemic oxygen transport and response to therapy in clinical shock.

Hormonal and Metabolic Responses to Glucose Infusion in Sepsis Studied by the Hyperglycemic Glucose Clamp Technique

Although nutritional support is vital to treatment of severe sepsis, the septic patient does not respond normally to glucose infusion. We have used the hyperglycemic glucose clamp technique to investigate the initial hormonal and metabolic responses of the septic patient to glucose under controlled conditions. The plasma glucose concentration was raised to and maintained at 12 mmol/liter for 2 hr in 12 septic patients and 11 normal controls. Glucose utilization, assessed from the amount infused, was significantly depressed in the patients, despite similar plasma insulin concentrations in the two groups. Forearm glucose uptake was similarly impaired. Despite very similar plasma free fatty acid concentrations in the two groups, which were suppressed equally by the glucose infusion, whole-body fat oxidation was elevated in the patients compared with the controls, and suppressed to a lesser extent in response to glucose. Glycerol and ketone body concentrations were elevated in the patients in keeping with a picture of accelerated release, clearance, and oxidation of fatty acids. Plasma cortisol, epinephrine, and norepinephrine concentrations were elevated in the septic patients in a severity-related manner, but not to high levels compared with experimental work. Norepinephrine showed no response to the glucose infusion in either group. Plasma glucagon concentrations were not significantly elevated in the septic patients. We conclude that the hyperglycemic glucose clamp provides a useful model for studying glucose intolerance in sepsis. Impaired glucose utilization in septic patients is associated with increased fat oxidation, although the hormonal basis for these changes is still unclear.

Serum leptin concentrations and their relation to metabolic abnormalities in human sepsis

Circulating leptin concentrations are raised in animal models of inflammation and sepsis. The purpose of this study was to determine the effect of sepsis on serum leptin concentration in humans and to examine the relationship between leptin and the metabolic consequences of sepsis. Resting energy expenditure, insulin sensitivity, and fasting serum leptin, plasma insulin, and cortisol concentrations were measured in 20 subjects with intra-abdominal sepsis and 20 healthy control subjects, before and during a 2-h period of euglycemic hyperinsulinemia. Fasting serum leptin concentrations were similar in septic and control subjects. In simple regression analysis, serum leptin concentrations correlated significantly with percent body fat in both septic patients ( r = 0.64, P < 0.005) and healthy subjects ( r = 0.75, P < 0.0001). Multiple regression analyses additionally indicated that percent body fat, fasting plasma insulin, and plasma cortisol, but not sepsis, were significant and independent determinants of serum leptin concentration. No relationship between leptin and resting energy expenditure or insulin sensitivity was identifiable. A major metabolic role for leptin in human sepsis therefore appears unlikely.Circulating leptin concentrations are raised in animal models of inflammation and sepsis. The purpose of this study was to determine the effect of sepsis on serum leptin concentration in humans and to examine the relationship between leptin and the metabolic consequences of sepsis. Resting energy expenditure, insulin sensitivity, and fasting serum leptin, plasma insulin, and cortisol concentrations were measured in 20 subjects with intra-abdominal sepsis and 20 healthy control subjects, before and during a 2-h period of euglycemic hyperinsulinemia. Fasting serum leptin concentrations were similar in septic and control subjects. In simple regression analysis, serum leptin concentrations correlated significantly with percent body fat in both septic patients (r = 0. 64, P < 0.005) and healthy subjects (r = 0.75, P < 0.0001). Multiple regression analyses additionally indicated that percent body fat, fasting plasma insulin, and plasma cortisol, but not sepsis, were significant and independent determinants of serum leptin concentration. No relationship between leptin and resting energy expenditure or insulin sensitivity was identifiable. A major metabolic role for leptin in human sepsis therefore appears unlikely.

A comparison of the effects of skeletal muscle injury and somatic afferent nerve stimulation on the response to hemorrhage in anesthetized pigs

The effect of skeletal muscle injury (SMI) on cardiovascular and O2 transport responses to hemorrhage (HS) were examined in anesthetized pigs. Bilateral hindlimb muscle was injured 75 minutes before HS was started at a rate of 0.75 mL/min.kg until a total of 30 mL/kg (40% estimated total blood volume) had been removed. The reductions in cardiac index (CI), left ventricular stroke work, and oxygen delivery (Do2) and the increase in plasma lactate concentration following HS were exacerbated by SMI such that although oxygen consumption was maintained after HS it fell after SMI + HS. The deleterious effect of SMI on the response to HS was greater than that recorded previously following somatic brachial nerve stimulation (BNS). Thus, in order to achieve a given reduction in CI and Do2 or a rise in Shock Index (heart rate divided by systolic blood pressure) to approximately 3, a blood loss of 40% was needed after HS; this was reduced to 36% by the addition of BNS, whereas a loss of only 29% was needed when SMI was introduced. The mechanism of the deleterious effect of SMI is unclear although a change in the distribution of regional blood flow and a rise in the critical oxygen delivery may be implicated.

Muscle wasting associated with endotoxemia in the rat: modification by the beta 2-adrenoceptor agonist clenbuterol.

A single injection of endotoxin (1 mg/kg, sc) in rats caused significant fever, body weight loss and reduction in gastrocnemius muscle mass, none of which was mimicked by pair-feeding. Infusion of endotoxin via osmotic minipump over five days caused transient fever and suppression of growth. Recovery of body weight was significantly enhanced by the administration of theβ2-adrenoceptor agonist clenbuterol (added to the diet at 4 mg/kg). In a separate experiment, injections of endotoxin (day 0 and day 2) caused significant reductions in body weight gain (42%), mass (9%) and protein content (13%) of gastrocnemius muscle over 3 days. Addition of clenbuterol to the diet reversed all of these effects but did not alter food intake or the febrile response to endotoxin. Clenbuterol caused large (20%) increases in the ratio of RNA to protein in muscle indicating that it may have stimulated protein synthesis.β2-adrenoceptor agonists may therefore be of value in preventingor inhibiting muscle atrophy associated with infection or injury.

Effects of the β2-adrenoceptor agonist, clenbuterol, on muscle atrophy due to food deprivation in the rat

The effects of a beta 2-adrenoceptor agonist, clenbuterol, on body weight and protein metabolism of gastrocnemius muscle, heart, and liver were studied in rats subjected to 50% food restriction or fasting. Food restriction by 50% for 7 days caused a complete cessation of growth and reductions in the mass, protein, and RNA content of muscle, heart, and liver. The ratio of RNA to protein content was also suppressed in muscle and heart, but not in liver. Fasting for 3 days caused loss of body weight (BW), reductions in the mass, protein, and RNA content, and the ratio of RNA to protein of gastrocnemius muscle, heart, and liver. Oral administration of clenbuterol (approximately 0.6 mg/kg BW/d) to food-restricted animals did not affect BW, but did increase in the mass, protein, and RNA content, and the ratio of RNA to protein of gastrocnemius muscle. The protein content of heart was also increased. Twice-daily injections of clenbuterol (2 mg/kg body weight/d) to fasting animals had no effect on BW or the mass or protein content of gastrocnemius muscle or liver, but both parameters were stimulated in heart. The results indicate that the anabolic action of clenbuterol are maintained when substrate availability is reduced by food restriction, but this effect is lost during severe protein and energy deficit (fasting).

Cardiovascular response to graded lower body negative pressure in young and elderly man

Lower body negative pressure (LBNP) reduces central venous pressure (CVP) and cardiac output. The elderly are reported to have a limited capacity to increase cardiac output by increasing heart rate (HR), are especially dependent on end diastolic volume to maintain stroke volume and therefore should be especially vulnerable to LBNP. The present study compared the effects of LBNP in the young and old. Stroke volume was assessed non‐invasively as stroke distance (SD) by aortovelography. Two groups of healthy male volunteers were studied: eight young (29.7 ± 2.0 years, mean ± S.E.M.) and nine old (70.1 ± 0.9 years). LBNP was applied progressively at 17.5, 35 and 50 mmHg in 20 min steps, with measurements taken during each steady state. There were similar, significant, falls in CVP in both groups. SD fell significantly in both groups from respective control values of 24.8 ± 1.6 and 16.6 ± 0.9 cm to 12.5 ± 1.3 and 8.9 ± 0.4 cm at a LBNP of 50 mmHg. Although SD in the elderly was significantly lower than in the young, the LBNP‐induced changes were not different between groups. Both groups produced similar significant increases in vascular resistance, HR, plasma vasopressin (AVP) and noradrenaline. Mean arterial blood pressure (MBP) and plasma adrenaline did not change significantly. Therefore healthy old men respond to LBNP in a similar manner to the young, although MBP and SD are regulated around different baselines in the two groups.

Catecholamine sensitivity in the rat femoral artery after microvascular anastomosis.

Tissue can demonstrate vasospastic instability after microvascular anastomosis. This study investigates the in vitro effect of increasing concentrations of phenylephrine on the rat femoral artery after microvascular anastomosis. Bilateral groin flaps based on the inferior epigastric artery were raised on 55 Wistar male rats. On the test side, a microvascular anastomosis was performed, but not on the control side. On days 2–12 postoperatively, the rats were sacrificed and the femoral arteries harvested and suspended in increasing concentrations of phenylephrine. The vascular tone on the test and control sides were recorded and compared. Increased sensitivity was found on the test side as compared with the control side (P = 0.000). This supersensitivity to phenylephrine was blocked by the addition of phentolamine and it is believed to be the result of sympathetic denervation, which occurs when the sympathetic fibers are cut during the harvesting of the flap. The resulting vascular instability is believed to contribute to flap failure.

Clenbuterol, a beta 2-adrenergic agonist, reverses muscle wasting due to scald injury in the rat.

The effects of clenbuterol, a beta 2-adrenergic agonist, on body weight, tissue masses, and protein and RNA contents were studied following scald injury (30 per cent TBSA) in the rat. While the masses of heart, liver and epididymal fat pads remained unaffected, significant reductions in gastrocnemius, plantaris and soleus muscle masses (approximately 11 per cent; P < 0.01) were observed following injury, none of which were mimicked by pair-feeding or could be attributed to dehydration. This muscle wasting was accompanied by significant reductions in protein and/or RNA content. Oral administration of clenbuterol (4 mg/kg diet) had no anabolic effects, either in the scalded animals or their pair-fed controls. While clenbuterol (12 mg/kg diet) did not affect the masses of heart and fat pads, increases in the wet weights (approximately 20 per cent), RNA (approximately 30 per cent) and protein content (approximately 20 per cent) of the gastrocnemius and plantaris muscles were observed in all animals; the magnitude of these effects was greater (P < 0.05) in the scalded animals than in their pair-fed controls. Clenbuterol had no effect on body weight but increased (P < 0.001) carcass water content. These data indicate that there is a selective mobilization of muscle protein and sparing of fat in the early phase following burn injury, and that beta 2-adrenergic agonists, such as clenbuterol, may be of therapeutic value in inhibiting or reversing muscle atrophy associated with thermal injury.

The effect of nociceptive stimulation on the changes in hemodynamics and oxygen transport induced by hemorrhage in anesthetized pigs.

The effects of somatic nociceptive afferent stimulation on aspects of cardiac function and oxygen transport were examined in a model of hemorrhage in anesthetized pigs. The brachial nerves were stimulated (BNS) alternately to obtain a rise in heart rate of 18% and in mean arterial pressure of 17%. This stimulation was started 75 minutes before the start of hemorrhage and maintained throughout and after the withdrawal of blood. The animals were bled at a rate of 0.75 ml/min.kg until a total of 30 ml/kg had been removed. At the end of hemorrhage the reductions in cardiac index (CI), stroke volume (SV), and left ventricular stroke work (LVSW) were greater in the BNS group compared with controls. The nociceptive stimulation also elicited greater reductions in oxygen delivery (DO2I) and oxygen consumption (VO2) and a greater rise in the arterial plasma lactate concentration. Thus it seems that nociceptive stimulation exacerbates the changes in systemic oxygen transport and cardiac function induced by hemorrhage.