Laboratory-Confirmed Metformin-Associated Lactic Acidosis

Introduction Metformin is considered the first line oral hypoglycaemic agent for the treatment of type 2 diabetes. We report three cases of prospectively identified laboratory confirmed metformin-associated lactic acidosis admitted to our intensive care unit. Case 1 72-year-old female presented with lactic acidosis; pH 6.7, lactate 22.6mmol/L with elevated Metformin levels of 4.9mg/L. Case 2 56-year-old female presented with lactic acidosis; pH 7.2 and lactate 14.8mmol/L. Metformin levels elevated at 3.9mg/L. Case 3 72-year-old female presented with lactic acidosis, pH 6.95 and lactate of 27.6mmol/L with elevated Metformin levels of 48.7mg/L. Results All three cases were admitted to the intensive care unit to receive supportive care. Despite CVVHD, two patients died. Discussion Metformin is considered the first line oral hypoglycaemic agent. Confirmation of this diagnosis often proves difficult due to the scarcity of laboratory testing. Our case series highlights the issues of inappropriate prescription in specific patient populations.

The allelic modulation of apolipoprotein E expression by oestrogen: potential relevance for Alzheimer's disease.

BACKGROUND: The epsilon4 allele of the apolipoprotein E (APOE) gene is a major genetic risk factor for Alzheimer's disease but appears to be associated with greater risk in women than in men. Some studies suggest that the level of APOE may of its own modulate the risk for Alzheimer's disease. Sex differences and an apparent benefit of oestrogen therapy suggest a role for oestrogen. APOE expression is influenced by oestrogen and oestrogen therapy may not benefit women bearing an APOE epsilon4 allele. These findings suggest an interaction between oestrogen and APOE in the Alzheimer's disease process. AIM: To explore the hypothesis that APOE expression is regulated by a genomic mechanism and is modified by the polymorphisms in APOE associated with risk for Alzheimer's disease. METHODS: In vitro binding studies were undertaken between oestrogen receptors and fragments of the human APOE gene. APOE gene expression was studied to investigate a possible functional interaction. RESULTS: APOE epsilon2/epsilon3/epsilon4 coding and -219 G/T promoter polymorphisms influenced binding to the oestrogen receptor and altered transcriptional activity in response to oestrogen. CONCLUSIONS: An allele dependent modulation of oestrogen induced regulation of APOE might be involved in the increased risk for Alzheimer's disease in women bearing an epsilon4 allele.

The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress.

The Memorial Symptom Assessment Scale (MSAS) is a new patient-rated instrument that was developed to provide multidimensional information about a diverse group of common symptoms. This study evaluated the reliability and validity of the MSAS in the cancer population. Randomly selected inpatients and outpatients (n = 246) with prostate, colon, breast or ovarian cancer were assessed using the MSAS and a battery of measures that independently evaluate phenomena related to quality of life. Symptom prevalence in the 218 evaluable patients ranged from 73.9% for lack of energy to 10.6% for difficulty swallowing. Based on a content analysis, three symptoms were deleted and two were added; the revised scale evaluates 32 physical and psychological symptoms. A factor analysis of variance yielded two factors that distinguished three major symptom groups and several subgroups. The major groups comprised psychological symptoms (PSYCH), high prevalence physical symptoms (PHYS H), and low prevalence physical symptoms (PHYS L). Internal consistency was high in the PHYS H and PSYCH groups (Cronback alpha coefficients of 0.88 and 0.83, respectively), and moderate in the PHYS L group (alpha = 0.58). Although the severity, frequency and distress dimensions were highly intercorrelated, canonical correlations and other analyses demonstrated that multidimensional assessment (frequency and distress) augments information about the impact of symptoms. High correlations with clinical status and quality of life measures support the validity of the MSAS and indicate the utility of several subscale scores, including PSYCH, PHYS, and a brief Global Distress Index. The MSAS is a reliable and valid instrument for the assessment of symptom prevalence, characteristics and distress. It provides a method for comprehensive symptom assessment that may be useful when information about symptoms is desirable, such as clinical trials that incorporate quality of life measures or studies of symptom epidemiology.

Molecular genetic studies of bipolar disorder and puerperal psychosis at two polymorphisms in the estrogen receptor alpha gene (ESR 1).

A number of lines of evidence point to the possible involvement of estrogen pathways in the pathophysiology of bipolar disorder in general and puerperal psychosis in particular. There is strong evidence from clinical, follow-up, and genetic studies to support the hypothesis that most cases of puerperal psychosis are manifestations of an affective disorder diathesis with a puerperal trigger and that genes influence susceptibility to both diathesis and trigger. The nature of the trigger is unknown but in view of the abrupt onset at a time of major physiological change it is widely believed that biological, probably hormonal, mechanisms are of paramount importance, with estrogen receiving the most attention to date. We have undertaken a case control association study of bipolar disorder and puerperal psychosis at two known polymorphisms within the estrogen receptor alpha gene (ESR 1) in a sample of 219 unrelated bipolar probands and 219 controls. We could exclude these polymorphisms from an important contribution to susceptibility to bipolar disorder with a high level of confidence. We found no support for the hypothesis that they contribute specific susceptibility to the puerperal trigger, but due to the small numbers of puerperal probands (n = 26) no firm conclusions can be drawn regarding their involvement in puerperal psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:850-853, 2000.

Molecular genetic approaches to puerperal psychosis.

Puerperal psychosis, an episode of mania or psychosis precipitated by childbirth follows approximately one in 1000 deliveries. The evidence of clinical, outcome and genetic studies supports the hypothesis that the majority of puerperal psychotic episodes are manifestations of an affective disorder diathesis with a puerperal trigger. Furthermore the available evidence supports the hypothesis that genes are involved in susceptibility to both diathesis and trigger. For complex genetic disorders such as affective illness there are marked benefits in focussing on a homogeneous subtype which allows a subset of hypotheses to be tested. Molecular genetic studies of puerperal psychosis provide an excellent example of this strategy, allowing a hierarchy of hypotheses concerning the involvement of neurosteroid pathways in pathophysiology to be tested. Puerperal psychosis results in considerable suffering to a woman and her family. Elucidating the pathophysiological basis of this disorder will lead to better prevention and treatment and, it is anticipated, inform research on affective disorders more generally.

Guidelines in the care of the dying cancer patient.

The care of patients in the final stages of cancer requires a high level of clinical vigilance and skill to ensure that the passage from life to death is as free from suffering as possible. Patients who are dying have a right to adequate relief of physical and psychological symptoms, and they and their families have a right to adequate support. The care of patients and their families requires (1) interdisciplinary cooperation of a healthcare team incorporating physicians, nurses, social workers, and other auxiliary supports, and (2) a high level of clinical flexibility to address the evolving needs of the patient and family. Participation in this process challenges the clinician's emotional resources and medical skills. There is, however, the potential for professional satisfaction in helping to orchestrate a "good death," because the relief of suffering is at the very heart of medicine. Familiarity with guidelines in the care of the dying can reduce the potential for distress in this important clinical endeavor.

A model of continuity of care for cancer patients with chronic pain.

A patient and family-centered, nurse-coordinated model is presented in which a collaborative approach among nurse, physician, and social worker is used. The team is based at a hospital or cancer center, but is oriented toward the community. In the model, the nurse is responsible for the day to day management of the patient's pain, and works with the patient, family, and community physicians and nurses in symptom control and supportive care.

Infection as a cause of rapidly increasing pain in cancer patients.

Rapid escalation of cancer-related pain is usually assumed to be due to progression of the neoplasm. Occult local infection is a poorly recognized alternative cause. We describe two patients who developed rapidly increasing pain that was determined in each case to be due to occult local infection. These cases suggest that all patients with rapid escalation of chronic cancer pain should undergo an evaluation to identify a cause of changing nociception, and that infection should be considered among the possible diagnoses. Lack of fever or leukocytosis does not exclude local infection, and empirical treatment with antibiotics is sometimes indicated.

Controversies in the long-term management of analgesic therapy in patients with advanced cancer.

The management of pain in the patient with advanced cancer requires comprehensive assessment and expertise in the application of many therapeutic techniques. Given the complexity of the problems posed by these patients, it is not surprising that most aspects of palliative care derive from personal anecdote and clinical consensus, rather than well-defined guidelines based on research findings. In the absence of such guidelines, unresolved issues and controversies abound. This review discusses some of the most important of these topics, which range from the overall system of care and quality of assessment to the specifics of pharmacotherapy and other modalities of treatment. In so doing, the rationale for some of the accepted clinical approaches can be clarified, others that are as yet little known can be highlighted, and the issues most in need of further investigation can be defined.

Delirium as a contributing factor to "crescendo" pain: three case reports.

Cancer patients occasionally experience periods of rapidly escalating pain--"crescendo" pain--that may present a challenge in assessment and management. Although these episodes are often associated with progressive neoplasm, any of a variety of other processes may be involved. Delirium is a potentially treatable and frequently unrecognized factor. We present three patients who illustrate this relationship between delirium and a crescendo pattern of cancer pain.

Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life.

There is a great variability among advanced cancer patients in the experience of symptoms and their impact on life's activities. A subgroup of difficult patients particularly tax the clinical skills and compassion of practitioners. Although the need for information about these patients is evident, their characteristics have not been explored heretofore. We describe our experience with such patients, a group referred to the Supportive Care Program of the Pain Service at Memorial Sloan-Kettering Cancer Center. Prevalence of pain and other symptoms, patterns of opioid use and routes of drug administration, and the prevalence of suicidal ideation and requests for euthanasia are discussed.

Cancer pain management with a controlled-release oral morphine preparation.

An open-label pilot study was conducted to assess the efficacy and acceptability of a controlled-release oral morphine formulation, MS Contin tablets, when administered "by the clock" two to three times daily as a substitute for opioids given on request to patients with pain caused by advanced cancer. Initially, four-hourly does of standard "immediate-release" oral morphine sulfate tablets were substituted for the patients' prior analgesic medication and titrated to individual needs. Forty of the 47 patients enrolled in the study were subsequently switched to an eight-hourly MS Contin regimen (three patients became too ill to continue the study, and four left the study during the immediate-release titration phase because of adverse reactions that may have been drug related). Small "rescue" doses of standard oral morphine were available to the patients, but they were taken infrequently. Twenty-one of the 37 patients maintained on the eight-hourly schedule consented to be treated with, and were subsequently stabilized on, MS Contin administered every 12 hr, with a reduction of over 20% in their average daily morphine dose. Most of the patients rated the controlled-release medication superior to the standard oral morphine tablets in terms of both convenience and adequacy of relief.

Implementing national standards for cancer pain management: program model and evaluation.

The purpose of this quasi-experimental (pre and posttest) study was to test a model pain management program (PMP) to implement the American Pain Society (APS) quality assurance standards for the management of acute and chronic cancer pain using a continuous quality improvement (CQI) approach to improve professionals' knowledge and skills, patient satisfaction, and to identify areas needing improvement. The sample consisted of 1210 nurse responses and 698 interviews of patients with pain during hospitalization at a major urban cancer center. The PMP provided a structure (standards), educational opportunities, and training in CQI methods. Outcome measures included a patient evaluation questionnaire and concerns checklist; nurse knowledge, attitude and barriers questionnaire; and focus groups to identify areas needing improvement. Significant improvements were found in patients' satisfaction, nurses' knowledge and attitude scores, and reductions in nurses' perceptions of barriers. Focus groups revealed the need for improved communication among disciplines about pain and better assessment of patients unable to self-report. The program met its goal of implementing the APS standards, educating nurses, and identifying "system" problems, and improving overall patient satisfaction.

Subcutaneous opioid infusions at home.

The ability to provide subcutaneous infusions in the home has had a major impact on patient care. The main indication for this approach in the cancer population is the need for prolonged parenteral administration of an opioid drug. Successful administration begins with proactive consideration of patient selection; choice of pump, drug, mode of infusion, and dosing schedule; the resources of the family and community health-care system; and cost and insurance coverage. Long-term management requires ongoing liaison among the hospital pain management team, home care infusion agency, and community physicians and nurses.

Current management of opioid-related side effects.

The optimal management of opioid-related side effects is hampered by a lack of comparative studies of management strategies. The prevalence of such side effects is influenced by the extent of disease, the patient's age, the presence of coexistent renal and hepatic disease, pulmonary disease, and cognitive dysfunction, a prior opioid history, use of polypharmacy, dose of opioid drug being administered, and the route of administration. The most common opioid-related side effects are constipation, sedation, nausea, vomiting, and cognitive disturbance. Less frequent side effects include urinary retention, perceptual distortion, respiratory depression, and myoclonus. In an era emphasizing quality of life in cancer care, clinicians need to be aware of (1) factors that influence the prevalence of opioid-related side effects, (2) effective management strategies, and (3) how to recognize when symptoms are opioid related as opposed to caused by other etiologies, such as the patient's disease process or treatment approaches. The use of validated instruments and repeated assessment enhances such an evaluation and subsequent treatment. This article delineates the current optimal management of opioid-related nausea and vomiting, constipation, cognitive side effects, myoclonus, and respiratory depression.

NCCN Practice Guidelines for Cancer Pain.

The overall approach to pain management encompassed in these guidelines is comprehensive. It is based on objective pain assessments, utilizes both pharmacologic and nonpharmacologic interventions, and requires continual reevaluation of the patient. The NCCN Cancer Pain Practice Guidelines Panel believes that cancer pain can be well controlled in the vast majority of patients if the algorithms presented are systematically applied, carefully monitored, and tailored to the needs of the individual patient.

Age and sex differences in strategies of coping and defense across the life span.

Age and sex differences in the use of coping and defense strategies were examined in life-span sample of 381 individuals. Participants responded to 2 self-report measures assessing mechanisms of coping and defense and measures assessing their level of cognitive complexity. Older adults used a combination of coping and defense strategies indicative of greater impulse control and the tendency to positively appraise conflict situations. Adolescents and younger adults used strategies that were outwardly aggressive and psychologically undifferentiated, indicating lower levels of impulse control and self-awareness. Women used more internalizing defenses than men and used coping strategies that flexibly integrated intra-and interpersonal aspects of conflict situations. Taken together, findings provide evidence for the age- and sex-specific use of strategies of coping and defense, suggesting that men and women may face different developmental tasks in the process toward maturity in adulthood.

Multidisciplinary care of the terminally ill patient.

This article discusses sedation, the assessment and management of physical symptoms, and symptom-assessment scales for the terminally ill patient. The evaluation of the ability of the family or community to care for a terminally ill patient in pain also is discussed.

Terminal care and bereavement.

Care of patients at the end of life requires a high level of clinical vigilance, compassion and skill. The involvement of the patient's primary neurologist in end-of-life care and into bereavement can be an invaluable comfort to the patient and family. An understanding of the techniques for assessing and anticipating patient and family needs and knowledge of the resources available is essential if the neurologist is to provide guidance in their care.

Development and validation of a patient needs assessment tool (PNAT) for oncology clinicians.

The Patient Needs Assessment Tool (PNAT) is an interviewer-rated scale that may be completed through a simple structured interview and screens cancer patients for potential problems in physical and psychosocial functioning. The instrument provides separate scores for physical, psychological, and social status, and can potentially clarify the types of interventions needed to address specific areas of dysfunction. Reliability and validity was tested in two studies that used prescreened patient videotapes and other materials to assess the performance of the PNAT in groups of oncology nurses, physicians, and social workers. The data demonstrate that subscale scores for the physical, psychological, and social dimensions have good inter-rater reliability and internal consistency (intraclass correlation coefficients of 0.71-0.97). Criterion and construct validity was suggested through high correlations of each subscale with the evaluation of expert raters (correlation coefficients of 0.85-0.95) and with scores on validated patient-rated instruments appropriate to the functional area. These analyses suggest that the PNAT is a valid scale for the assessment of a range of functional disturbances in the cancer population.