Quality and outcomes in anaesthesia: lessons from litigation.

Healthcare litigation in the UK continues to grow at an alarming rate, with claims against anaesthetists and critical care physicians increasing each year. This has led to a huge financial burden for the taxpayer and a sharp increase in professional indemnity fees for individual doctors. Although such litigation should provide valuable information to educate practitioners and reduce future similar claims, there appear to be significant barriers preventing important lessons from being learned. Detailed learning opportunities are available only to the healthcare providers being sued or the expert witnesses employed to analyse the claims. Most practitioners have to rely on indemnifiers' case reports, closed-claim analyses, and ad hoc publications for information. In this review, we suggest ways in which important lessons from litigation could be brought to the attention of all clinicians. Currently, most clinicians are unable to determine whether key components of their practice such as consent, clinical decision-making, and documentation are of an acceptable standard for legal scrutiny. By reporting outcomes of Coroners' inquests, clinical and criminal negligence cases, and referrals to the General Medical Council, it would be hoped that more explicit standards of performance could be derived. Ultimately, this may not only improve patient safety, but protect practitioners from unjustifiable claims. Finally, given the critical importance of experts in the above process, we believe that a system for professional registration and regulation should be explored to ensure that they offer accurate, representative, and unbiased opinions and have the appropriate expertise in the subject matter to be analysed.

Mechanisms of immune lysis of red blood cells in vitro. I. Paroxysmal nocturnal hemoglobinuria cells.

The effect of five different reactions which activate complement (antibody activation, reduction in ionic strength, acidification, cobra venom factor (CoF) activation, and inulin activation) upon normal and PNH cells was investigated, using normal serum and serum devoid of the fourth component of complement (C4) activity from patients with hereditary angioneurotic edema (HANE) as a source of complement. Both normal and HANE serum lysed paroxysmal nocturnal hemoglobinuria (PNH) cells when complement was activated by acidification, CoF and inulin, indicating that the terminal steps of complement were activated in the absence of C4, presumably by the alternate or properdin pathway. Normal but not HANE serum lysed cells coated with anti-I, indicating that complement was activated by the C1-dependent classic pathway. HANE serum partially supported lysis by serum at reduced ionic strength, indicating that the activation of terminal complement components had occurred through both of the pathways of activation. The amount of the third component of human complement (C3) which was bound to the membrane of lysed and unlysed cells by these procedures was determined by anti-C3 absorption and was found to differ for each method of complement activation. In general, more C3 was bound to lysed cells than to unlysed cells. For given conditions, more was bound to PNH cells than to normal cells. However, very much less bound C3 was required for lysis of the PNH cells than for lysis of normal cells. These two phenomena, especially the latter, account for the marked lysis of PNH cells when complement is activated. Normal cells treated with AET (aminoethylisothiouronium bromide) did not bind more C3 than untreated cells and the lysed cells had less bound C3 than lysed PNH cells.

A physiological approach to the assessment of disease activity in rheumatoid arthritis.

A method is described for assessing the in vivo oxygen consumption and lactate production rates of human knee joints. It is based on the rate of fall of P(o2) and the rate of rise in lactate concentration in an intra-articular saline pool after interruption of the circulation to the joint with an arterial tourniquet. Studies in 5 control patients with degenerative joint disease and 29 patients with rheumatoid arthritis showed a 2- to 3-fold higher mean oxygen uptake rate and a 10- to 12-fold higher mean lactate appearance rate in the saline in the rheumatoid joints with severe disease compared to the control joints. These metabolic variables correlated with tissue metabolic demand as estimated in synovial biopsies. (133)Xe washout from the intra-articular space, which reflects joint circulatory flow, showed a 3-fold greater mean washout rate from the rheumatoid joints (48 studies) than control joints (7 studies) with extensive overlap between the two groups. (133)Xe washout rate correlated with knee joint inflammation estimated both clinically and histologically. After synovectomy in four patients, the operated knee showed a greater fall in lactate production than the opposite knee in three of these patients. Neither knee joint oxygen uptake nor (133)Xe washout rate changed significantly. Intra-articular corticosteroid injection (eight patients) resulted in decreased lactate production and a decreased (133)Xe washout rate in the injected knee and variable results in the untreated knee. Oxygen uptake again was unchanged after therapy.

The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus.

Activation of the mitogen-activated protein kinase (MAPK) cascade recently was discovered to play an important role in synaptic plasticity in area CA1 of rat hippocampus. However, the upstream mechanisms regulating MAPK activity and the downstream effectors of MAPK in the hippocampus are uncharacterized. In the present studies we observed that hippocampal MAPK activation is regulated by both the PKA and PKC systems; moreover, we found that a wide variety of neuromodulatory neurotransmitter receptors (metabotropic glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors, and beta-adrenergic receptors) couple to MAPK activation via these two cascades. In additional studies we observed that PKC is a powerful regulator of CREB phosphorylation in area CA1. MAPK plays a critical role in transcriptional regulation by PKC, because MAPK activation is a necessary component for increased CREB phosphorylation in response to the activation of this kinase. Surprisingly, we also observed that MAPK activation is necessary for PKA coupling to CREB phosphorylation in area CA1. Overall, these studies indicate an unexpected richness of diversity in the regulation of MAPK in the hippocampus and suggest the possibility of a broad role for the MAPK cascade in regulating gene expression in long-term forms of hippocampal synaptic plasticity.

The effect of calcium ions on the activated partial thromboplastin time of heparinized plasma.

The effect of calcium chloride (CaCl2) on the activated partial thromboplastin time (aPTT) of heparinized plasma was studied. The aPTT ratio (heparinized plasma:control plasma) increased as the CaCl2 concentration to recalcify the plasma was increased from 15 to 35 mmol/L CaCl2. Platelet-poor plasma from patients receiving intravenous heparin, and in vitro heparinized plasmas from either coumarinized patients or plasma depleted of the vitamin K-dependent factors, displayed the calcium-dependent increase in the aPTT ratio. The magnitude of the calcium-dependent change in the aPTT ratio was similar for the three partial thromboplastins studied. Heparinized blood collected in 3.2% and 3.8% citrate demonstrated the calcium-dependent increase in the aPTT ratio. The authors have also studied the effect of the divalent cations (Ca+2, Mg+2, Zn+2, and Sr+2) on the anti-Factor Xa activity of heparin to determine whether the calcium-dependent increase in the aPTT was due to an increase in the anti-Factor Xa activity. The anti-Factor Xa activity of heparin was measured using chromogenic substrate S-2251, purified Factor Xa, and excess antithrombin III. The anti-Factor Xa activity of heparinized plasma increased 2.4-2.8-fold as the divalent cation concentration was increased from 0-5 mmol/L. Similar results were obtained using purified bovine Factor Xa, antithrombin III, and heparin in the absence of plasma. These results suggest that divalent cations play an important role in modulating heparin's anticoagulant activity in vitro. In addition, the CaCl2 concentration used to recalcify plasma is an important variable that modifies heparin sensitivity of the aPTT. Furthermore, divalent cations play an important role in regulating the anti-Factor Xa activity of heparin in vitro.

Complications of arterial puncture in anticoagulated patients.

Thirteen patients who were receiving heparin in therapeutic doses had complications after femoral or brachial arterial puncture as follows: hematomas resulting in skin slough or infection in two, neuropathies of the median nerve in two and of the femoral nerve in two, and ischemia of the forearm muscles in seven. Since arterial puncture to determine blood gases in patients anticoagulated for pulmonary emboli can be dangerous, alternate means to establish the diagnosis are recommended. Early recognition and treatment of complications are essential.

Biochemical changes in the collagen of the palmar fascia in patients with Dupuytren's disease.

The palmar fascial tissues of more than 400 patients with Dupuytren's disease were studied biochemically and compared with normal tissue obtained from more than 100 patients who were undergoing hand surgery for other reasons. No alterations of the molecular structure or the state of macromolecular aggregation of the collagen in Dupuytren's disease were detected by wide or low-angle x-ray diffraction studies or by transmission electron microscopy. Major biochemical changes in the palmar fascia affected by Dupuytren's disease included increased collagen and hexosamine contents and the presence of galactosamine in the most severely involved tissue. Type-III collagen, which is virtually absent from normal adult palmar fascia, was abundant in the tissue of patients with Dupuytren's disease. Post-translational modifications included a very elevated hydroxylysine content, an increase in the total number of reducible cross-links, and the appearance of hydroxylysinohydroxynorleucine (virtually absent from normal palmar fascia) as the major reducible cross-link. Even palmar fascia from patients with Dupuytren's disease that appeared grossly and histologically normal showed the same biochemical changes, albeit to a lesser extent. All of these biochemical changes are similar to those that occur during the active stages of connective-tissue wound repair. This includes the rapid synthesis and turnover of collagen which leads to newly synthesized, immature collagen being more abundant in the involved tissue than in normal tissue. There is no evidence that the gross, macroscopic contracture of the palmar fascia in Dupuytren's disease is due to shortening, plication, or contraction of the collagen fibrils or fibers present in the tissue at the onset of the disease or synthesized during its development. Instead, we propose that the gross contracture (shortening) of the palmar fascia in Dupuytren's disease is due to an active cellular process that progressively draws the distal extremities of the affected tissue closer together at the same time that the original tissue is being replaced. The result of these two processes is simply a shorter, smaller piece of tissue fabric containing collagen molecules, fibrils, and fibers of normal length and organization, but with pretranslational and posttranslational modifications similar to those observed in collagens during the active stages of connective-tissue repair in general.

MAPK regulation of gene expression in the central nervous system.

Long-term potentiation (LTP), a cellular model for long-term memory, is generally acknowledged to consist of both a short-term phase that is characterized by a dependence on autonomous protein kinase activity, and a long-term phase that is characterized by a dependence on changes in gene expression and new protein synthesis. Similarly, long-term memory exhibits a dependence on gene expression and altered protein synthesis. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) cascade plays a role in both LTP and long-term memory. The MAPK cascade has heretofore largely been studied in the context of cell division and proliferation and as such, mechanisms for the regulation of gene expression by the MAPK cascade have received considerable attention. Given the possible role of altered gene expression in the late phase of LTP and in long-term memory, we evaluated the capacity of the MAPK ERK (extracellular signal-regulated kinase) to regulate phosphorylation of the transcription factor cAMP response element binding protein (CREB) in hippocampal area CA1. Our studies indicate a critical role for the MAPK cascade in the regulation of CREB phosphorylation in the hippocampus.

Effects of an in-house coordinator and practitioner referral rather than proxy referral on tissue donation rates.

INTRODUCTION: Timely referral of patients following asystolic death to an organ procurement organization (OPO) may increase tissue donation rates. Lack of education of health care providers and nonphysicians (admitting department) about timely referral to the OPO following asystolic death may adversely affect tissue donation rates. We hypothesized that using an in-house donation coordinator for provider education and changing the responsibility for calling the OPO from the admitting department to the licensed independent practitioner (LIP) declaring death would increase timely referral and tissue donation rates. METHODS: An education program was developed in 2005 by a newly hired in-house coordinator to highlight the importance of tissue donation. In addition, to improve timely referrals to the OPO after death, the instructions accompanying the working copy of the death certificate were altered to require the patient's LIP to call the OPO within 1 hour of death (early 2007). Rates for both timely referrals and tissue donors were modeled by a Poisson regression model with a log link function. RESULTS: Timely referral rates rose from 48% before the interventions to 72% after the intervention (P < .0001). The number of tissue donors per number of referrals also increased significantly (P = .025) over that period. CONCLUSIONS: An in-house donation coordinator initiated education program and LIP referral rather than referral by other parties following asystolic death results in higher tissue donation rates.

The membrane abnormalities in paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) cells are characterized by an abnormal membrane which interacts abnormally with normal serum complement. These abnormal reactions occur at two levels of the sequence: 1) All abnormal PNH cells fix more C3 than normal cells for a given activation of complement; 2) PNH III cells are more readily lysed by a given number of assembled terminal complexes. The nature of the lesion yielding these abnormal reactions is not known.

The variability of hemolysis in the cold agglutinin syndrome.

The amount of lysis effected by cold agglutinins is directly related to the ability of the antibody to initiate complement activation. This ability is modified by the concentration of antibody, its thermal amplitude (the highest temperature at which the antibody will react with the cell), the degree to which antibody fixation is modified by the presence of complement components (particularly C3) on the membrane, and the degree to which antibody, once fixed, is able to fix the components of complement. In vitro measurement of these factors correlates with the rate of hemolysis in vivo.