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C J Hinds

Publications and source records attributed to C J Hinds.

At least 37 records · Page 2Linked to original sources
PubMed1998

Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin.

Inhibitors of nitric oxide synthase (NOS) attenuate the circulatory failure caused by endotoxin, but the role of NO in the development of multiple organ dysfunction and the relative contribution of NO produced by endothelial NOS and inducible NOS (iNOS) to organ injury remains unclear. Here we report for the first time that 1400W, a novel and highly selective inhibitor of iNOS activity, attenuates the delayed hypotension as well as the rise in the plasma levels of nitrite/nitrate caused by endotoxin in the rat. Inhibition of iNOS activity with 1400W administered either before or 2 h after endotoxin injection did not, however, attenuate the hepatocellular injury, renal dysfunction, or pancreatic injury in this model. Similarly, administration of another selective inhibitor of iNOS activity, L-NIL, 2 h after endotoxin injection abolished the rise in nitrite/nitrate and attenuated the delayed hypotension caused by endotoxin, but failed to ameliorate organ injury. Thus, selective inhibition of iNOS activity with 1400W attenuates the circulatory failure induced by endotoxin in the rat, but fails to influence the degree of organ injury/dysfunction.

Amidines↗
PubMed1998

Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by endotoxin.

The nuclear enzyme poly(ADP-ribose) synthetase (PARS) is activated by DNA strand breakage, caused, for example by nitric oxide (NO), peroxynitrite, or oxygen-derived free radicals. Activation of PARS can cause intracellular energy depletion and cell death in vitro and may play a role in the circulatory and organ failure caused by endotoxin (LPS). Here we investigate the effects of various chemically distinct inhibitors of PARS activity (3-aminobenzamide, nicotinamide, 1,5-dihydroxyisoquinoline) on circulatory failure and organ dysfunction caused by LPS in the rat. Administration of endotoxin caused circulatory failure, acute renal dysfunction, hepatocellular injury and dysfunction, pancreatic injury, elevation of plasma lactate levels, and overproduction of NO. None of the PARS inhibitors used reduced the circulatory failure, the renal dysfunction, rise in lactate, or the overproduction of NO caused by LPS. Although 1,5-dihydroxyisoquinoline (ISO) attenuated the rises in the serum levels of bilirubin, alanine aminotransferase (ALT) (indicators of liver injury/dysfunction), and lipase (indicator of pancreatic injury); a similar effect was also observed with the vehicle for ISO, dimethyl sulfoxide (DMSO), which is a well known scavenger of hydroxyl radicals. Thus, the beneficial effects of ISO are unlikely to be due to inhibition of PARS activity, but may be due to the scavenging of free radicals by its vehicle DMSO. Activation of PARS does not contribute to the circulatory failure, renal dysfunction, lactic acidosis, or the overproduction of NO and is unlikely to contribute to the liver injury/dysfunction caused by endotoxic shock in the rat.

Animals↗
PubMed1998

Liver microsomal transport of glucose-6-phosphate, glucose, and phosphate in type 1 glycogen storage disease.

The transport of glucose-6-phosphate (G6P), glucose, and orthophosphate into liver microsomes, isolated from six patients with various subtypes of type 1 glycogen storage disease (GSD), was measured using a light-scattering method. We found that G6P, glucose, and phosphate could all cross the microsomal membrane, in four cases of type 1a GSD. In contrast, liver microsomal transport of G6P and phosphate was deficient in the GSD 1b and 1c patients, respectively. These results support the involvement of multiple proteins (and genes) in GSD type 1. The results obtained with the light-scattering method are in accordance with conventional kinetic analysis of the microsomal glucose-6-phosphatase system. Therefore, this technique could be used to directly diagnose type 1b and 1c GSD.

Adult↗
PubMed1998

Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis.

We report the emergency and prolonged use of etomidate to control circulating cortisol levels in a patient with Cushing's syndrome secondary to ectopic ACTH production from a pancreatic islet cell tumor. Duodenal perforation and peritonitis complicated an episode of salmonella septicemia, precluding the use of conventional oral medical adrenolytic therapy. Endogenous cortisol secretion was abolished by parenteral etomidate, allowing serum cortisol levels to be controlled with an iv infusion of hydrocortisone over an 8-week period in intensive care before definitive pancreatic surgery.

Adenoma, Islet Cell↗
PubMed1997

The role of IGFs in catabolism.

The hypercatabolic response to trauma, extensive surgery and sepsis is characterized by an increased metabolic rate, severe muscle wasting and a negative nitrogen balance. This process of 'autocannibalism' may be in part a consequence of a disordered growth hormone (GH)/insulin-like growth factor (IGF) axis. In this chapter the normal physiology of the GH/IGF axis is first briefly reviewed. This is followed by a discussion of the changes that accompany fasting and catabolic illness, the effects of IGF-1 administration in health and disease and a comparison of the effects of IGF-1, GH and insulin on catabolism. Although initial investigations of IGF-1 administration in animals and human volunteers have often been encouraging, studies in catabolic patients have so far proved disappointing. Combined treatment with GH, IGF-1 (and insulin) or with IGF-1 and its major binding protein, may prove more effective, especially when used in conjunction with nutritional supplements such as glutamine.

Animals↗
PubMed1997

Oxygen transport patterns in patients with sepsis syndrome or septic shock: influence of treatment and relationship to outcome.

OBJECTIVE: To investigate the relationship between oxygen transport patterns and outcome in patients with sepsis syndrome or septic shock managed according to two different treatment regimens. DESIGN: Retrospective study of a subgroup of patients with sepsis syndrome or septic shock taken from a randomized, prospective, controlled trial. SETTING: General intensive care units in a teaching and a district general hospital. PATIENTS: Seventy-eight patients classified according to predetermined criteria as having sepsis syndrome or septic shock were drawn retrospectively from a larger study group of 109 consecutive patients considered to be at risk for developing multiple organ failure. INTERVENTIONS: All patients received volume expansion to an optimal pulmonary artery occlusion pressure. If the therapeutic goals (cardiac index of > 4.5 L/min/m2, oxygen delivery [DO2] of > 600 mL/min/m2, and oxygen consumption [VO2] of > 170 mL/min/m2) were not achieved with fluids alone, patients were randomized to either a control group or a treatment group. In the treatment group, dobutamine (5 to 200 micrograms/kg/min) was administered to increase cardiac index and DO2 until all three goals were simultaneously achieved. In the control group, dobutamine was administered only if the cardiac index was < 2.8 L/min/m2. In both groups, norepinephrine was infused to maintain mean arterial pressure at 80 mm Hg. MEASUREMENTS AND MAIN RESULTS: Hemodynamic, oxygen transport, and lactate measurements were made at the time of admission to the study, at the time of optimal volume administration, at 1, 2, 4, 8, 12, 16, 20, and 24 hrs, then every 6 hrs for the next 24 hrs, and at least every 8 hrs thereafter. The time at which all therapeutic goals were first achieved simultaneously or the time of maximal DO2 was identified and termed "tmax." Survivors from both the control and treatment groups significantly (p < .001) increased cardiac index and DO2 in response to maximal resuscitation, and despite an associated decrease in oxygen extraction (p < .01), there was a significant (p < .01) increase in VO2. In nonsurvivors from both groups, despite significant increases in cardiac index (p < .05) and DO2 (p < .01) at tmax, oxygen extraction decreased (p < .01) and VO2 remained unchanged. DO2 and VO2 were significantly lower (p < .05) at tmax in nonsurvivors than in survivors from both groups. Persistently high lactate concentrations were characteristic of nonsurvivors. CONCLUSIONS: Survivors of sepsis syndrome or septic shock are characterized by an ability to increase both DO2 and VO2. In contrast, nonsurvivors typically have reduced cardiac reserve, they fail to increase VO2 following resuscitation, and when delivery is enhanced with aggressive inotropic support, oxygen extraction falls. These patterns of response were similar in both treatment and control groups, although the magnitude of the changes was exaggerated in the treatment group. These observations may help to explain the findings by some investigators that treatment aimed at achieving survivor values of cardiac index, DO2, and VO2 fails to improve outcome when instituted following admission to intensive care.

Adrenergic alpha-Agonists↗
PubMed1997

Administration of human recombinant insulin-like growth factor-I in critically ill patients.

OBJECTIVES: To study the pharmacokinetics of a single subcutaneous dose of recombinant human insulin-like growth factor-I (IGF-I) in patients with systemic inflammatory response syndrome in the intensive care unit (ICU). To evaluate the effects of exogenous recombinant human IGF-I on circulating concentrations of IGF-I binding protein-1 (IGFBP-1), IGF-I binding protein-3 (IGFBP-3), and growth hormone in the critically ill patient; to assess the safety of the subcutaneous administration of 40 microg/kg of recombinant human IGF-I in these patients; and to investigate any effect this dose might have on nitrogen balance, creatinine clearance, and serum electrolyte and lipid concentrations. DESIGN: Open-labeled, noncontrolled, prospective, single-dose study of eight fully evaluable ICU patients with systemic inflammatory response syndrome. SETTING: ICUs in a teaching hospital and a linked district general hospital in England. PATIENTS: Nine patients were examined, eight of whom were fully evaluable. INTERVENTIONS: Subcutaneous administration of 40 microg/kg of recombinant human IGF-I. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken 24 hrs before the subcutaneous injection of 40 microg/kg of recombinant human IGF-I, and for 48 hrs thereafter. Urine was collected throughout this period. Serum concentrations of IGF-I, IGFBP-1, IGFBP-3, growth hormone, and insulin were measured by radioimmunoassay. IGF-I concentrations (median and range) increased significantly above baseline values (35 ng/mL [20 to 144]) from 15 mins (p < .02) until 10 hrs (p < .02) after injection of recombinant human IGF-I. Peak IGF-I concentrations were sustained from 2 hrs (90.5 ng/mL [23 to 228]) to 5 hrs (88.5 ng/mL [29 to 300]). By 24 hrs, circulating IGF-I concentrations had returned to baseline values. Baseline IGF-I concentrations were extremely low, and although peak values were three times greater, these values only approached the fifth percentile of defined reference ranges for normal values. Compared with values in less seriously ill patients, maximum IGF-I concentrations were reached earlier, the elimination half-life was shorter, clearance was more rapid, and the apparent volume of distribution was similar. IGFBP-3 concentrations also increased after recombinant human IGF-I injection, and at 3 to 4 hrs were significantly elevated, from 30 mins (p = .04) to 8 hrs (p = .04). There was marked between-patient variability in changes in circulating IGF-I, and IGFBP-1, and IGFBP-3 concentrations. More severely ill patients had the lowest circulating IGF-I concentrations and the least response to exogenous recombinant human IGF-I. Elevated baseline circulating growth hormone concentrations (2.3 ng/mL, range 0.8 to 4 [5.1 mU/L, 1.5 to 8]) were significantly depressed from 4 hrs (0.5 ng/mL, 0.5 to 1.5 [1 mU/L, 1 to 3], p = .01) to 6 hrs (0.8 ng/mL, 0.5 to 4 [1.5 mU/L, 1 to 8], p = .02) after recombinant human IGF-I administration. CONCLUSION: We observed no adverse effects (e.g., hypoglycemia) that could be attributed to recombinant human IGF-I therapy.

Adult↗
PubMed1997

Desensitization of the inflammatory response in humans: changes in response to cardiopulmonary bypass.

Although circulating levels of interleukin 8 (IL-8), a potent pro-inflammatory chemokine, and many other inflammatory mediators increase in response to cardiopulmonary bypass, only a small proportion of patients develop a clinically significant systemic inflammatory response. The natural mechanisms that control the inflammatory response are poorly understood. To investigate the role of IL-8 in a human inflammatory model, 15 adult patients undergoing cardiopulmonary bypass for elective coronary artery bypass grafting were studied. Following reperfusion, plasma IL-8 levels increased significantly from 58 pg/mL (pre-bypass) and 66 pg/mL (after 20 min of bypass) to 98 pg/mL (p = .02 and .04, respectively), but this was accompanied by a concomitant threefold decrease in the IL-8 binding affinity of circulating neutrophils (Dissociation constant (KL) post-reperfusion/KL pre-bypass = 3.2; KL post-reperfusion/KL after 20 min of bypass = 2.8). IL-8-triggered release of myeloperoxidase and elastase by peripheral blood neutrophils ex vivo was also down-regulated following reperfusion. There were no significant changes in beta 2 integrin expression or inositol polyphosphate metabolism of peripheral blood neutrophils. These changes in receptor affinity and neutrophil responsiveness to IL-8 may represent an important in vivo regulatory mechanism which serves to prevent excessive tissue injury from inflammatory triggers.

Antigens, CD↗
PubMed1996

Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease.

OBJECTIVES: To describe the sequential changes in the circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with induction of a specific protease directed against insulin-like growth factor binding protein 3 and to relate these changes to outcome. DESIGN: Prospective, descriptive study. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: Eighteen heterogeneous critically ill patients, requiring ventilatory support. INTERVENTIONS: Serial daily blood samples were collected until death or discharge from the ICU. In five patients, samples were also obtained on the ward before discharge from the hospital. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins 1, 2, and 3 were measured by radioimmunoassay. After 5 days, insulin-like growth factor binding protein 3 concentrations were measured on alternate days. Alterations in binding of insulin-like growth factor-I to insulin-like growth factor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting. Circulating concentrations of insulin-like growth factor-I and insulin-like growth factor-II were low and remained low throughout the 7-day study period. Insulin-like growth factor binding protein 1 concentrations were initially increased to within the fasting range, but subsequently decreased. There was considerable variability in insulin-like growth factor binding protein 2 concentrations, but generally, concentrations were at the upper end of the normal range throughout. Insulin-like growth factor binding protein 3 concentrations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the presence of a protease directed against insulin-like growth factor binding protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also studied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and cessation of protease activity over a period of 33 days. In another patient, a nonsurvivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 remained low and protease activity persisted until the patient died 38 days after admission to the ICU. CONCLUSIONS: Critical illness is associated with low circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin-like growth factor binding protein 3. In survivors, recovery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessation of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.

Adolescent↗
PubMed1996

Reduction in circulating IGF-I and hepatic IGF-I mRNA levels after caecal ligation and puncture are associated with differential regulation of hepatic IGF-binding protein-1, -2 and -3 mRNA levels.

Sepsis is characterized by a severe shift in metabolism, characterized by low IGF-I levels. We have studied the influence of caecal ligation and puncture (CLP) on the levels of circulating IGF-I and hepatic IGF-I and IGF-binding protein (IGFBP)-1, -2 and -3 mRNA in adult male Wistar rats (n = 12) and compared it with sham-operated rats (n = 6). In order to exclude anorexia-induced changes we also studied animals pair-fed to both groups. IGF-I levels were measured by RIA. Steady-state hepatic IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 mRNA levels were measured by Northern blot analysis using specific rat cDNA probes. Food intake averaged 13.0 +/- 2.0 g/day in the sham-operated rats fed ad libitum during the study period, with a sharp decline in food intake in the CLP animals (2.3 +/- 1.3 g/day). After CLP, there was a significant reduction in circulating IGF-I levels (467.2 +/- 50.9 micrograms/l) compared with sham-operated animals (924.0 +/- 75.3 micrograms/l; P = 0.04) or those pair-fed to the CLP rats (612.5 +/- 52.9 micrograms/l; P = 0.04). Total hepatic IGF-I mRNA levels were significantly reduced (2.57 +/- 0.05 densitometric units (DU) after CLP compared with the sham-operated group (2.71 +/- 0.04); P = 0.04), or their pair-fed controls (2.75 +/- 0.08 DU; P < 0.05). Hepatic IGFBP-3 mRNA levels were lower after CLP (0.37 +/- 0.04 DU) than in the sham-operated animals (0.66 +/- 0.09 DU; P = 0.04) or their pair-fed controls (0.61 +/- 0.05 DU; P = 0.04). On the other hand, hepatic IGFBP-2 mRNA levels were increased after CLP (0.91 +/- 0.11 DU) compared with sham-operated animals (0.28 +/- 0.06 DU; P = 0.01) or with their pair-fed controls (0.22 +/- 0.02; P = 0.01), as were hepatic IGFBP-1 mRNA levels (CLP animals 0.95 +/- 0.11 DU; sham-operated 0.30 +/- 0.04 DU, P = 0.01; pair-fed 0.30 +/- 0.02 DU, P = 0.01). No significant difference between sham-operated animals and their pair-fed controls was observed in circulating IGF-I levels (888.0 +/- 109.3 micrograms/l; P = not significant (N.S.)), hepatic mRNA levels for IGF-I (2.72 +/- 0.06 DU; P = N.S), IGFBP-3 (0.71 +/- 0.07 DU; P = N.S.), IGFBP-2 (0.25 +/- 0.07 DU; P = N.S.) or IGFBP-1 (0.27 +/- 0.06 DU; P = N.S.). In summary, after CLP there was a reduction in both circulating and hepatic IGF-I mRNA levels associated with a specific and differential regulation of hepatic IGFBP-1, -2 and -3 mRNA levels. Although we cannot eliminate a possible effect of surgical stress combined with malnutrition, our results suggest that these changes are a specific effect of sepsis rather than simply a result of surgical stress or poor nutrition alone.

Animals↗
PubMed1994

Elevation of systemic oxygen delivery in the treatment of critically ill patients.

BACKGROUND: Elevation of systemic oxygen delivery and consumption has been associated with an improved outcome in critically ill patients. We conducted a randomized trial to determine whether boosting oxygen delivery by infusing the inotropic agent dobutamine would improve the outcome in a diverse group of such patients. METHODS: On the basis of previously published recommendations, we established the following goals: a cardiac index above 4.5 liters per minute per square meter of body-surface area, oxygen delivery above 600 ml per minute per square meter, and oxygen consumption above 170 ml per minute per square meter. If these goals were not achieved with volume expansion alone, patients were randomly assigned to a treatment or control group. The treatment group received intravenous dobutamine (5 to 200 micrograms per kilogram of body weight per minute) until all three goals had been achieved. Dobutamine was administered to the control group only if the cardiac index was below 2.8 liters per minute per square meter. RESULTS: A total of 109 patients were studied. In nine patients the therapeutic goals were achieved with volume expansion alone; all nine patients survived to leave the hospital. Fifty patients were randomly assigned to the treatment group, and 50 to the control group. During treatment, there were no differences between the two groups in mean arterial pressure or oxygen consumption, despite a significantly higher cardiac index and level of oxygen delivery in the treatment group (P < 0.05). Although the predicted risk of death during hospitalization was 34 percent for both groups, the in-hospital mortality was lower in the control group (34 percent) than in the treatment group (54 percent) (P = 0.04; 95 percent confidence interval, 0.9 to 39.1 percent). CONCLUSIONS: The use of dobutamine to boost the cardiac index and systemic oxygen delivery failed to improve the outcome in this heterogeneous group of critically ill patients. Contrary to what might have been expected, our results suggest that in some cases aggressive efforts to increase oxygen consumption may have been detrimental.

Adult↗
PubMed1994

Clinical validation of a radionuclide detector to measure ejection fraction in critically ill patients.

The use of a new non-imaging nuclear probe (Cardioscint) capable of continuous online monitoring of left ventricular function is described in critically ill patients undergoing mechanical ventilation. Ejection fraction, measured by the Cardioscint, was compared with that measured by echocardiography. The mean difference was -1.1% (95% confidence interval -2.9 to +0.6%). Mean difference +/- 2 SD was +10.6 to -12.8% (95% confidence intervals +7.5 to 13.6% and -15.8 to -9.0%, respectively). Examples of fluid loading and inotropic support showed comparable changes in stroke counts measured by the Cardioscint and stroke index measured by thermodilution. The Cardioscint is a practical bedside method for continuous or repeated measurement of ejection fraction and for assessing the response to therapeutic interventions in critically ill patients.

Adult↗
PubMed1993

Preliminary observations on the neuromuscular abnormalities in patients with organ failure and sepsis.

OBJECTIVE: To estimate the incidence and nature of neuromuscular abnormalities in a representative group of ITU patients. DESIGN: Prospective sequential study. SETTING: Teaching hospital ITU. PATIENTS: 23 patients who eventually stayed > 7 days on ITU who had no contraindication to muscle biopsy and whose relatives gave informed consent. MEASUREMENTS AND RESULTS: Muscle histopathology, neurophysiological studies, record of all drugs administered, APACHE II score, organ system failure score, presence or absence of sepsis, clinical evaluation of neuromuscular problems, time to hospital discharge. Heterogeneous neuromuscular abnormalities were present in 22 out of 23 patients studied and included axonal neuropathy, denervation, generalised fibre atrophy, non-specific myopathy and necrotising myopathy. CONCLUSION: Neuromuscular abnormalities are almost invariable in longstay intensive care patients and the resulting weakness may seriously delay hospital discharge. Various abnormalities were seen but no obvious aetiological factors were identified. The origin of the abnormalities is probably multifactorial.

Adolescent↗