IRON DEFICIENCY ANAEMIA IN GENERAL PRACTICE: PRESENTATIONS AND INVESTIGATIONS

Twenty-six patients over the age of 50 years with proven iron deficiency anaemia were identified, investigated and followed up in general practice over a five-year period. The anaemia was symptomatic in 50% of patients but only 20% had symptoms related to the gut. Faecal occult blood testing was positive in five patients only and negative tests occurred in three patients with significant disease, including one caecal carcinoma. All patients agreed to oesophagogastroduodenoscopy (OGD) and fibreoptic sigmoidoscopy carried out on the same occasion. In eight patients, significant abnormalities were found on OGD and in two patients on sigmoidoscopy. Four patients declined barium enema examinations, two of whom had significant OGD abnormalities. Barium enema examination of the other 22 patients showed polyposis of the colon and a caecal carcinoma and initially missed one carcinoma of the caecum which was found subsequently. The likelihood of finding significant disease in iron-deficient patients over 50 years of age is high and should be assumed to be due to blood loss into the gut. Investigation by OGD, sigmoidoscopy and barium enema in the first instance seems warranted and is a condition that can be safely managed by the GP. (Br J Clin Pract 1997; 51(2) : 78-80)     

Erythropoietin kinetics in rats: generation and clearance

Detailed studies to analyze the early events of erythropoietin (Ep) secretion and clearance were performed in a rat model using a double antibody radioimmunoassay. Ep clearance was determined following intravenous injection of 1 mL of Ep-rich plasma, 1,080 mU/mL, obtained from phlebotomized rats. Analysis revealed a disappearance curve that conformed to a two-compartment model with an alpha half-life t1/2 of 3.6 minutes and a beta t1/2 of 86 minutes. The volume of distribution was similar to the calculated plasma volume. In anephric animals, there was no change in the plasma clearance rate or the volume of distribution. Rapid Ep secretion was elicited by a single 15 mL/kg phlebotomy (hematocrit decrement 45% to 30%), so that levels reached 20 to 30 times baseline (524 +/- 76 v 24 +/- 7 mU/mL) at five hours, whereas they plateaued for at least 33 hours. The increase in the rate of secretion was geometric, from 9.9 mU/h baseline secretion to 429 mU/h. These data identify a very sensitive and rapidly responsive system for Ep modulation in the rat.     

Endotracheal intubation in the ICU

Endotracheal intubation in the ICU is a high-risk procedure, resulting in significant morbidity and mortality. Up to 40% of cases are associated with marked hypoxemia or hypotension. The ICU patient is physiologically very different from the usual patient who undergoes intubation in the operating room, and different intubation techniques should be considered. The common operating room practice of sedation and neuromuscular blockade to facilitate intubation may carry significant risk in the ICU patient with a marked oxygenation abnormality, particularly when performed by the non-expert. Preoxygenation is largely ineffective in these patients and oxygen desaturation occurs rapidly on induction of anesthesia, limiting the time available to secure the airway. The ICU environment is less favorable for complex airway management than the operating room, given the frequent lack of availability of additional equipment or additional expert staff. ICU intubations are frequently carried out by trainees, with a lesser degree of airway experience. Even in the presence of a non-concerning airway assessment, these patients are optimally managed as a difficult airway, utilizing an awake approach. Endotracheal intubation may be achieved by awake direct laryngoscopy in the sick ICU patient whose level of consciousness may be reduced by sepsis, hypercapnia or hypoxemia. As the patient’s spontaneous respiratory efforts are not depressed by the administration of drugs, additional time is available to obtain equipment and expertise in the event of failure to secure the airway. ICU intubation complications should be tracked as part of the ICU quality improvement process.One of the highest risk procedures carried out in the ICU is tracheal intubation. Significant complications occur in up to 40% of cases, with severe hypotension occurring in 10 to 25%, severe hypoxemia in 25% and cardiac arrest in 2% [1–4]. The incidence of death or brain damage is far higher following complications of intubation in the ICU than complications in the operating room (OR) [5]. This higher degree of harm has been attributed to the patients’ pre-existing hypoxemia and to hemodynamic instability [4, 5], but lack of recognition of the differences between intubation in the ICU versus the OR may play a role.Endotracheal intubation in the OR and ICU are different procedures, although this is not always appreciated. The OR intubation usually involves a physiologically stable patient in an optimal environment. In contrast, the ICU intubation usually occurs in an unstable patient often with a period of time (albeit sometimes brief) to allow for evaluation and planning, and in an environment not always ideally suited to airway management. A significant proportion of ICU intubations are performed by relatively junior trainees, with or without supervision [1, 3, 5]. Unlike the OR where the primary objective is the induction of anesthesia, in the ICU the procedural objective is to secure the airway as a life-saving intervention in a patient with respiratory failure.Airway management guidelines developed for anesthesia have been applied to the ICU environment, although the ICU patient is very different physiologically, and induction of anesthesia with resultant apnea is potentially harmful in this patient group. The stable patient about to undergo elective surgery may safely experience 6 to 8 minutes of apnea before developing significant hypoxemia, if adequately preoxygenated [6]. The ICU patient is usually intubated because of a pre-existing oxygenation or ventilation abnormality. Preoxygenation is usually ineffective in raising their oxygen saturation [4], and they will desaturate rapidly on induction of apnea, in some cases in as little as 30 seconds. The patient with a marked metabolic acidosis requires an adequate minute ventilation to maintain an acceptable pH, which is lost during a prolonged apneic intubation.The definition of a ''difficult airway'' is vague, encompassing difficulty in bag-mask ventilation, multiple intubation attempts, inadequate glottic view and complications [7], and is influenced by new fiberoptic technologies allowing an improved view. Prediction of a potentially difficult airway is based on history and a bedside assessment of anatomy [7]. Given the different timeframe available for intubation of the ICU patient, the airway assessment developed for the OR may not be applicable to the ICU. Furthermore, these methods to identify a difficult airway are not highly sensitive or specific, and unexpected difficult airways still occur. These can usually be managed in the OR, with access to additional expert staff, specialized equipment, and with the 6 to 8 minute buffer time, none of which are generally available in the ICU. With patients in the OR, bag-mask ventilation can usually provide adequate ventilation and oxygenation. However, the ICU patient with significant acute respiratory distress syndrome has reduced lung compliance, making bag-mask ventilation less effective. It is not unexpected, therefore, that intubation with techniques inducing apnea will result in the high complication rates cited above.Given these physiological and situational differences between ICU and OR intubations, a safe approach would be to consider all ICU intubations as ''difficult airways''. Difficult airway algorithms begin with a decision of ''forced to act'', which necessitates an immediate best possible attempt, or ''not forced to act'', where the main tactic is an awake intubation. The safest approach for an ICU intubation is to consider an awake attempt. This is in contrast to the current practice where the initial approach is almost always induction of deep sedation with or without paralysis (inducing apnea). A rationale given for the common use of sedation and neuromuscular blockade during intubation in the critically ill is that paralysis improves the rate of successful first or second attempts, and that the complication rate of intubation increases with multiple attempts [8]. This circular reasoning fails to acknowledge that the reason for complications with multiple attempts is, in fact, the presence of drug-induced apnea producing hypoxemia.In some agitated patients the awake approach will not be possible. However, a remarkable number of ICU patients will accept intubation with little more than topical anesthetic - some sedation usually being provided by the accompanying sepsis, hypoxia or hypercapnia. Direct laryngoscopic view of the vocal cords has been shown to be possible in the majority of well patients with minimal sedation [9]. Awake intubation sometimes implies complex instrumentation with which junior trainees are not familiar (for example, fiberoptic bronchoscopy) and so awake intubation becomes the purview of the expert. However, there is little to be lost by an initial look in an awake and breathing patient with a conventional laryngoscope and a local anesthetic spray. Either the patient will be able to be intubated, or if they are a little resistant but the airway looks easy, a small amount of sedative may facilitate the procedure. If the airway appears impossible for that operator, the procedure can be abandoned awaiting expert assistance - the patient remains breathing and is no worse off than prior to the intubation attempt. Recent studies and commentary suggest a role for awake videolaryngoscopy in the patient with a difficult airway [10] - hopefully a practice that will soon migrate to the ICU.     

Current treatment for alcohol withdrawal [editorial]

The online version of the original article can be found at     

Expansion of the growth fraction in multiple myeloma with alkylating agents

Patients with IgG multiple myeloma underwent serial studies of tumor cell kinetics including (1) estimation of the total body myeloma cell number (TBMC), (2) measurement of the myeloma cell tritiated thymidine labeling index (LI), and (3) calculation of the total number of myeloma cells undergoing DNA synthesis. Intermittent courses of chemotherapy with cycle-non-specific agents such as melphalan resulted in a marked increase in the LI of myeloma cells in patients who had a 75% reduction in TBMC. The long "plateau" phase of partial remission of myeloma in these patients was associated with a continued high LI: this suggests that the plateau resulted from a balance between the cytoreductive effects of chemotherapy and expansion of the growth fraction (GF) of the tumor. Preliminary attempts to capitalize therapeutically on this expansion of the GF in several patients included administration of the cycle-active agents vincristine and cytosine arabinoside. Vincristine appeared to induce a further reduction in tumor in several patients, although cytosine arabinoside appeared to be ineffective despite clear evidence of its inhibition of DNA synthesis in myeloma cells in vivo. Further clinical studies of the effects of cycle-active drugs on myeloma appear to be warranted; however, successful exploitation of the dynamic change in myeloma cell kinetics with chemotherapy will require the use of cycle-active agents with marked selective toxicity for myeloma cells.     

Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells

Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs showing strong in vitro activity against the human immunodeficiency virus type-1 (HIV-1). Each drug, however, has significant toxicity against normal marrow progenitor cells that frequently proves dose-limiting in patients. In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested as single agents and in combination against normal myeloid (CFU-GM) and erythroid (BFU- E) colony forming cells in a standard methylcellulose culture assay. The data were analyzed using a quantitative computerized analysis based on the median-effect principle and the isobologram equation as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for BFU-E and CFU-GM inhibition was then compared with previously measured in vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in vitro. We demonstrate that (a) the drugs are strongly synergistic in inhibiting marrow progenitor cell growth and that this synergism occurs at drug levels that are within the range of measured plasma levels in phase I clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug concentrations in combination that synergistically inhibit bone marrow progenitors are much higher than those required to inhibit HIV-1 replication in vitro, and (d) the anti- HIV-1 effect for the combination of AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or rIFN-alpha 2a alone as indicated by the combination index and the dose-reduction index. These data suggest that substantially lower doses of AZT and rIFN-alpha than those currently being tested in clinical trials might not only maintain a strong synergistic anti-HIV-1 effect but might also avoid significant hematologic toxicity.     

Neutrophil elastase produces 52-kD and 30-kD glucocorticoid receptor fragments in the cytosol of human leukemia cells

Characterization of glucocorticoid receptors in leukemia cells is important to understand mechanisms of glucocorticoid resistance but has been impeded by receptor fragmentation in cytosol extracts. We recently found that formation of 52- and 30-kilodalton (kD) glucocorticoid receptor fragments in cytosol of leukemia cells is due to proteolysis and is blocked by diisopropylfluorophosphate (DFP). In the present study, we identify a 28-kD serine protease in cytosol of leukemia cells that binds [3H]DFP and correlates with the formation of 52- and 30-kD receptor fragments. This protease is immunoprecipitated by antiserum to neutrophil elastase. Limited digestion of [3H]dexamethasone-21-mesylate- labeled receptors by purified neutrophil elastase produces 52- and 30- kD receptor fragments. Receptor fragmentation in the cytosol of leukemia cells in inhibited by methoxysuccinyl-alanyl-alanyl-prolyl- valyl-chloromethylketone, a highly specific inhibitor of neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid cell suspension provides sufficient elastase to produce receptor fragmentation. Our findings indicate that neutrophil elastase is responsible for receptor fragmentation in the cytosol of leukemia cells. The neutrophil elastase may be endogenous to the leukemia cells or may come from neutrophils that contaminate leukemia cell suspensions.     

Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro

The recently cloned c-mpl ligand, thrombopoietin (Tpo), has been extensively characterized with regard to its ability to stimulate the growth, development, and ploidy of megakaryocyte progenitor cells and platelet production in vitro and in vivo. Primitive hematopoietic progenitors have been shown to express c-mpl, the receptor for Tpo. In the present study, we show that Tpo efficiently promotes the viability of a subpopulation of Lin-Sca-1+ bone marrow progenitor cells. The ability of Tpo to maintain viable Lin-Sca-1+ progenitors was comparable to that of granulocyte colony-stimulating factor and interleukin-1, whereas stem cell factor (SCF) promoted the viability of a higher number of Lin-Sca-1+ progenitor cells when incubated for 40 hours. However, after prolonged (> 40 hours) preincubation, the viability- promoting effect of Tpo was similar to that of SCF. An increased number of progenitors surviving in response to Tpo had megakaryocyte potential (37%), although almost all of the progenitors produced other myeloid cell lineages as well, suggesting that Tpo acts to promote the viability of multipotent progenitors. The ability of Tpo to promote viability of Lin-Sca-1+ progenitor cells was observed when cells were plated at a concentration of 1 cell per well in fetal calf serum- supplemented and serum-depleted medium. Finally, the DNA strand breakage elongation assay showed that Tpo inhibits apoptosis of Lin-Sca- 1+ bone marrow cells. Thus, Tpo has a potent ability to promote the viability and suppress apoptosis of primitive multipotent progenitor cells.