Dynamic preload markers to predict fluid responsiveness during and after major gastrointestinal surgery: an observational substudy of the OPTIMISE trial.

BACKGROUND: Stroke volume variation (SVV) and pulse pressure variation (PPV), termed dynamic markers of preload responsiveness, may predict the response to i.v. fluid in critically ill patients. However, the predictive accuracy of these variables during gastrointestinal surgery remains uncertain. METHODS: Observational study of patients aged ≥50 yr undergoing major gastrointestinal surgery, enrolled in the OPTIMISE trial. Patients received six 250 ml fluid challenges with i.v. colloid solution (three during and three after surgery), while SVV and PPV were measured using the LiDCOrapid monitor (LiDCO Ltd, UK). Fluid responsiveness was defined as a stroke volume increase ≥10%. Area under the receiver operating characteristic curve was calculated with 95% confidence intervals. Adjustment for covariates was performed by regression modelling and a clustering method was used to adjust for intra-patient correlation. RESULTS: One hundred patients were recruited between August 2010 and October 2012. Five hundred and fifty-six fluid challenges were administered and 159 (28.6%) were associated with increased stroke volume. The predictive value of both variables was poor during surgery [SVV 0.69 (0.63-0.77); PPV 0.70 (0.62-0.77)], and also after surgery [SVV 0.69 (0.63-0.78); PPV 0.64 (0.56-0.73)]. The findings were similar when analysed according to whether patients were mechanically ventilated [SVV 0.68 (0.63-0.77); PPV 0.69 (0.61-0.77)] or breathing spontaneously [SVV 0.69 (0.61-0.77); PPV 0.63 (0.56-0.72)]. Predictive value improved slightly in a sensitivity analysis excluding outlier values of SVV and PPV. CONCLUSIONS: In this study, the predictive accuracy of SVV and PPV for fluid responsiveness was insufficient to recommend for routine clinical use during or after major gastrointestinal surgery.

Mortality and utilisation of critical care resources amongst high-risk surgical patients in a large NHS trust.

Previous reports describe a population of non-cardiac surgical patients at high risk of complications and death. Outcomes are sub-optimal for such patients, perhaps in part related to inadequate provision or ineffective utilisation of critical care resources. In this study, data describing 26,051 in-patient non-cardiac surgical procedures performed in a large NHS Trust between April 2002 and March 2005 were extracted from local databases. Of these procedures, 2 414 (9.3%) were high risk with an overall mortality rate of 12.2% and a prolonged hospital stay (high-risk population median (IQR) 16 (9-30) days vs standard risk 3 (2-6) days). Mortality rates for specific procedures were consistent with UK averages. However, only 852 (35.3%) high-risk patients were admitted to a critical care unit at any stage after surgery. Of 294 high-risk patients who died, only 144 (49.0%) were admitted to a critical care unit at any time and only 75 (25.6%) of these deaths occurred within a critical care area. Mortality rates were high amongst patients discharged and readmitted to critical care (37.7%) and amongst those admitted to critical care following initial postoperative care on a standard ward (29.9%). These data suggest that the outcome of high-risk general surgical patients could be improved by adequate provision and more effective utilisation of critical care resources.

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.

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.

Effects of intravascular volume expansion on the cardiovascular response to naloxone in a canine model of severe endotoxin shock.

The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement. Animals were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion and treatment was instituted one hour after the endotoxin bolus. In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone-treated dogs. In volume-replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall. These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.

A new canine model of endotoxin shock.

A new canine model of endotoxin shock has been developed in which spontaneous recovery of cardiovascular function is largely prevented, the haemodynamic effects of anaesthesia are minimized and intravascular volume replacement is given. This model has been evaluated using two groups of five adult mongrel dogs anaesthetized with alpha-chloralose and breathing spontaneously. Animals in one group were anaesthetized, instrumented and given Escherichia coli (E. coli) endotoxin intravenously, whilst those in the control group were subjected only to anaesthesia and instrumentation. E. coli endotoxin was given to dogs in the shock group as a bolus dose of 5 mg kg-1 followed by a continuous infusion at 2 mg kg-1 h-1. This produced immediate, severe, cardiovascular depression, with precipitous falls in mean arterial pressure (MAP), cardiac index (CI), stroke index (SI) and left ventricular (LV) dp/dt max. There were associated increases in systemic and pulmonary vascular resistances. Arterio-venous oxygen content difference (C(a-v)O2) increased after induction of shock, and animals developed a progressive metabolic acidosis. Increasing haemoconcentration occurred, as evidenced by a rising haematocrit (PCV). Hypovolaemia was reflected by a concurrent fall in pulmonary capillary wedge pressure (PCWP). One hour after induction of shock, intravascular volume replacement was given in the form of a colloidal gelatin solution, as a bolus dose of 10 ml kg-1, followed by a continuous infusion at 10 ml kg-1 h-1. Volume replacement reversed haemoconcentration, restored PCWP and produced some haemodynamic improvement, although in general, severe cardiovascular depression persisted throughout a three hour observation period. This severe endotoxin shock model has proved to be stable, reproducible and economical. It provides a useful preliminary test for new methods of treatment in hypodynamic endotoxin shock, as well as allowing investigation of acute metabolic and physiological changes.

Characterization of circulating pro-opiomelanocortin-related peptides in human septic shock.

The nature of circulating pro-opiomelanocortin (POMC)-related peptides was investigated in patients with a diagnosis of septic shock. Also, changes following administration of methylprednisolone were monitored using established chromatographic techniques and three radioimmunoassays directed towards the N-terminal, mid-portion and C-terminal regions of the precursor. Adrenocorticotrophin and beta-endorphin-like peptides were identified in the circulation. By 60 min after a pharmacological dose of methylprednisolone (30 mg/kg) concentrations of these peptides were reduced and continued to fall up to 180 min. beta-Lipotrophin and N-terminal POMC(1-76) were also detected by the beta-endorphin and gamma 3-MSH assays respectively. The concentrations of these peptides were noticeably reduced only after 180 min. The 31,000 Da MSH/ACTH/beta-endorphin (POMC) and the 22,000 Da MSH/ACTH precursors were also present in the circulation in septic shock and their concentrations increased following steroid treatment.

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.

The induction of specific proteases for insulin-like growth factor-binding proteins following major heart surgery.

Insulin-like growth factors (IGF-I and IGF-II) circulate bound to specific high-affinity binding proteins (IGFBPs). Recent evidence has shown that in pregnancy and severe illness, specific proteases modify these binding proteins, reducing their affinity for IGFs. We have studied 12 patients, undergoing elective coronary artery vein-bypass graft surgery, for the appearance of these proteases and have demonstrated the induction of two independent, heat-labile, cation-dependent proteases. Proteolytic activity directed against IGFBP-3 was detected in all patients between 24 h and 5 days after surgery; the second IGFBP-4 specific protease was active 1 h after sternotomy. The total IGF-I levels were found to decrease following surgery, with the IGF-I distribution in the plasma being radically altered from that seen prior to the operation. One day after the operation the majority of the IGF-I, instead of being bound in the relatively inert 150 kDa complex, was associated with the smaller binding proteins which are more readily accessible to the tissues. These findings are in contrast to pregnancy where, despite similar proteases, the majority of the IGF-I remains in the 150 kDa complex. The alteration seen in IGF-I distribution after surgery did not appear to be a direct result of the IGFBP-3 proteolytic activity or an effect of the addition of heparin to the circulation. The potential increase in bioavailability of IGFs caused by the alteration in carrier protein may play a pivotal role in countering the catabolic state induced by surgery.

Plasma levels of neuropeptide tyrosine Y (NPY) are increased in human sepsis but are unchanged during canine endotoxin shock despite raised catecholamine concentrations.

Alterations in levels of adrenal vein and circulating immunoreactive neuropeptide tyrosine Y (NPY), as well as systemic catecholamine concentrations, have been investigated in the dog after endotoxin administration. Eighteen dogs were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. Severe shock was produced by the administration of a large bolus of Escherichia coli endotoxin followed by a continuous infusion. In two further animals the left lumbar adrenal vein was cannulated and an intermittent choke allowed retrograde sampling of the adrenal effluent. The production of hypodynamic shock was associated with marked increases in systemic catecholamine concentrations but there were no consistent changes in adrenal vein or systemic immunoreactive NPY levels. In contrast, circulating concentrations of immunoreactive NPY were markedly raised above the normal range in five patients with septic shock.

Biochemical characterization of circulating Met-enkephalins in canine endotoxin shock.

The alterations in arterial, venous and adrenal vein levels of immunoreactive Met-enkephalins following endotoxin administration have been investigated in dogs by direct measurement and gel filtration chromatography. Animals were anaesthetized with alpha-chloralose and allowed to breath spontaneously. The left lumbar adrenal vein, limb vein and femoral artery were cannulated for blood sampling. Severe shock was produced by the administration of a large bolus of E. coli endotoxin followed by a continuous infusion. The production of endotoxin shock was associated with significant increases in adrenal vein and systemic venous plasma immunoreactive Met-enkephalin levels. Forty-five minutes after induction of endotoxin shock arterial immunoreactive Met-enkephalin levels were generally higher than baseline values. In resting anaesthetized animals a large 31,000 molecular weight form of Met-enkephalin, presumably proenkephalin, was found in plasma obtained from the adrenal vein, systemic and pulmonary circulations. Following endotoxin this enkephalin-containing peptide still predominated in arterial and venous plasma, whereas in the adrenal vein the proportion of Met-enkephalin immunoreactivity attributable to this large peptide fell. This was associated with the appearance of increasing amounts of smaller molecular forms (18,000, 8000, 3-5000 molecular weight and the pentapeptide itself). In this model enkephalin-containing peptides were not biochemically modified by their passage through the lungs.

Differential expression of suppressors of cytokine signalling genes in response to nutrition and growth hormone in the septic rat.

GH treatment during critical illness and sepsis may increase mortality. A family of negative regulators of cytokine signalling, the suppressors of cytokine signalling (SOCS), have been characterised. SOCS provide a mechanism for cross-talk between the cytokine receptors, including GH. Here, we have investigated the impact of nutrition and GH treatment on GH receptor, SOCS1, SOCS-2, SOCS-3 and cytokine-inducible SH2-containing protein (CIS) hepatic mRNA expression in a rat model of sepsis, caecal ligation and puncture (CLP). Four groups of rats were studied: control (food given ad libitum, n=7), CLP only (n=8), CLP and total parenteral nutrition (TPN) (n=9), and CLP, TPN and GH (n=10). CLP rats underwent surgery and 18 h later received saline or TPN or TPN+GH for 6 h before they were killed. Serum IGF-I levels were lower in all CLP groups (P<0.001). The combination of TPN and GH treatment increased IGF-I levels compared with the saline-treated CLP rats (P<0.01), but IGF-I levels remained lower than control animals (P<0.001). GH receptor and GH-binding protein expression in liver was reduced in animals subjected to CLP and was unaffected by nutrition or GH treatment. Hepatic SOCS-1 was detectable in normal rats, induced in all CLP animals but was unaffected by nutrition and GH. Hepatic SOCS-2 expression was difficult to detect in normal and CLP rats but was greatly induced in CLP rats treated with GH. Hepatic SOCS-3 expression was only just detectable in the control group but was elevated in all CLP groups and unaffected by nutrition and GH. Hepatic CIS expression was difficult to detect in normal rats, was not induced by CLP but was induced by both nutrition and GH. In conclusion, CLP induced low IGF-I levels associated with increased expression of SOCS-1 and SOCS-3, both of which are known to inhibit GH receptor signalling. GH induced SOCS-2 and CIS in the CLP rat despite resistance with respect to IGF-I generation, and parenteral feeding induced CIS in the CLP rat. Thus, there is potential for a complex interaction between GH and cytokine signalling at the level of SOCS expression whereby the inflammatory response may alter GH signalling and GH may influence the inflammatory response.

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.

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.

A cell wall component from pathogenic and non-pathogenic gram-positive bacteria (peptidoglycan) synergises with endotoxin to cause the release of tumour necrosis factor-alpha, nitric oxide production, shock, and multiple organ injury/dysfunction in the rat.

The incidence of sepsis and septic shock due to gram-positive organisms has increased dramatically over the last two decades. Interestingly, many patients with sepsis/septic shock have both gram-positive and gram-negative bacteria present in the bloodstream and these polymicrobial or "mixed" infections often have a higher mortality than infection due to a single organism. The reason for this observation is unclear. The aim of this study was to investigate whether cell wall fragments from gram-positive and gram-negative bacteria could synergise to cause the release of cytokines, shock, and organ injury/ dysfunction in vivo. Male Wistar rats were anaesthetised and received an intravenous bolus of vehicle (saline), lipopolysaccharide (LPS) from Escherichia coli (0.1 mg/kg), peptidoglycan (Pep G) from Staphylococcus aureus (S10 mg/kg), co-administration of LPS (0.1 mg/kg) and PepG from S. aureus (10 mg/kg), LPS (10 mg/kg), PepG from Bacillus subtilis, or co-administration of LPS and PepG from B. subtilis. Blood pressure and heart rate were monitored for 6 h before plasma samples were taken for the measurement of TNF-alpha, total nitrite, and biochemical indices of organ injury. Peptidoglycan from both pathogenic (S. aureus) and non-pathogenic (B. subtilis) gram-positive bacteria synergised with endotoxin to cause formation of TNF-alpha, nitrite, shock, and organ injury. Synergism between PepG and LPS may partly explain the high mortality associated with mixed bacterial infections, as well as the deleterious effects of translocation of bacteria, or their cell wall components from the gut lumen in patients with sepsis.

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.

Response of critically ill patients to treatment aimed at achieving supranormal oxygen delivery and consumption. Relationship to outcome.

STUDY OBJECTIVE: To evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport variables (cardiac index [CI] > 4.5 L/min/m2, oxygen delivery [DO2] > 600 ml/min/m2, and oxygen consumption [VO2] > 170 ml/min/m2) in a heterogenous group of critically ill patients and to assess its relationship to outcome. DESIGN: Patients were divided retrospectively into two groups. Group 1 (n = 15) achieved supranormal values for CI, DO2 and VO2 simultaneously during the first 24 h. Group 2 (n = 17) failed to achieve these goals simultaneously at any time point. SETTING: General intensive care units in a teaching and a district general hospital. PATIENTS: Thirty-two patients at risk of developing multiple organ failure were studied prospectively. INTERVENTIONS: Patients received volume expansion and then, if necessary, dobutamine (5 to 200 micrograms/kg/min) to increase CI and DO2 until all three goals were achieved simultaneously. RESULTS: In group 2, target VO2 could never be reached despite the fact that 11 (65 percent) patients achieved target CI and DO2 simultaneously. In this group, lactate levels did not fall and 16 patients died. In contrast, in group 1, attainment of all goals was associated with a significant reduction (p < 0.05) in blood lactate levels, and all but one of these patients survived. The persistently raised lactate levels in group 2 were associated with significantly higher venous oxygen saturation (SvO2) and lower oxygen extraction ratio (OER); in these patients, SvO2 rose and OER fell in response to increases in DO2. CONCLUSION: These results suggest that failure to increase VO2 was related predominantly to an inability of the tissues to extract or utilize oxygen rather than a failure to increase DO2. These findings support the hypothesis that in order to survive a critical illness, patients must achieve a high level of VO2. An inability to do so is reflected in persistently elevated blood lactate levels and an extremely poor prognosis.

Prolonged neurogenic weakness in patients requiring mechanical ventilation for acute airflow limitation.

We describe three patients who required mechanical ventilation for severe acute exacerbations of obstructive airways disease. When treatment with sedatives and muscle relaxants was withdrawn, they exhibited profound generalized weakness and consequently required prolonged ventilation despite resolution of the airway obstruction. Clinical features were variable, but none of the patients developed failure of other organs and infection was confined to the lungs. All had electrophysiologic evidence of a predominantly motor axonal syndrome. One patient in whom sensory action potentials were abnormal may represent an unusually severe case of critical illness neuropathy occurring in the absence of systemic sepsis and multiple organ failure. In the other two cases, this diagnosis is made less likely by the complete absence of sensory involvement and in these patients the lesion appeared to be either in the most distal portion of the motor neuron or at the neuromuscular junction. In all three patients, resolution was slow but eventually complete. The etiology of the condition is not clear, but it seems to be distinct from the acute myopathy previously described in asthmatics who had received mechanical ventilation. It is important to recognize this phenomenon to avoid erroneous conclusions about the likelihood of the patient recovering from ventilator dependence. A prolonged weaning period is to be expected in such cases.

Observations on the haemopoietic response to critical illness.

Peripheral blood cytopenias are common in patients receiving intensive care, particularly in those with multiple organ failure. To assess the contribution of bone marrow hypoplasia in such patients 44 bone marrow samples from 24 patients under intensive care were studied by standard morphological techniques and by the granulocyte-macrophage colony forming cell (GM-CFC) assay. Frequently observed morphological abnormalities in the bone marrow included the following: (i) a reduction in overall cellularity in seven patients, with a progressive decrease in most patients studied sequentially; (ii) an increase in the number of actively phagocytic macrophages; and (iii) a disruption of normal bone marrow architecture with the accumulation of intercellular hyaluronic acid glycosaminoglycan. Mean GM-CFC growth was significantly reduced when compared with that in a group of normal controls. In four of five patients studied sequentially GM-CFC growth became subnormal in association with a reduction in bone marrow cellularity. Inhibitory serum factors were not identified. These morphological abnormalities are similar to the changes observed in gelatinous degeneration of the bone marrow. In both situations disruption of the haemopoietic microenvironment, with the accumulation of hyaluronic acid proteoglycan, may be an important factor in the inhibition of haemopoietic progenitor cell growth. The proliferation of macrophages, by the release of a variety of cytokines or reactive oxygen intermediates, may also be implicated in impaired haemopoiesis and the development of disordered erythropoiesis.

Self-instruction and assessment in techniques of intensive care using a computer model of the respiratory system.

There are considerable logistical difficulties involved in providing an adequate training programme for each new doctor when starting intensive care. One solution is to use an interactive computer terminal and provide programmes for self-instruction and assessment. Using a computer model of the respiratory system linked to a computer-assisted instructional driver we have developed instructional exercises on the management of artificial ventilation and the treatment of respiratory failure. Each teaching session contains explanatory text, multiple choice questions and model simulations. The student can interact with the simulations, appropriate assistance being provided when required, while his answers are marked and assessed with further explanation when necessary. The use of computer models adds a new dimension to computer-assisted learning techniques and is particularly applicable to intensive care medicine.