Stress of Dying is not Suppressed by High-dose Morphine or by Dementia

Abstract

Hypothalamo-pituitary-adrenal (HPA)-axis activation is a response of the organism to psychological and physical stress, resulting in elevated levels of glucocorticoids, mainly cortisol in humans. In our previous studies we found post-mortem blood and cerebrospinal fluid (CSF) cortisol levels to be up to 20-fold higher than in vivo levels. Since clinical observations point to similar strong elevations of cortisol in fatally ill patients, we suggested that the high post-mortem cortisol levels might be due to the stress during the process of dying. We hypothesized that if the cortisol rise during dying is due to the psychological stress of the impending death, then the rise in cortisol should be inversely proportional to the degree of dementia, and that high-dose morphine giving analgesia, sedation, and sleep would suppress this response. Therefore, we measured the cortisol levels by radioimmunoassay (RIA) in the post-mortem CSF of 85 Alzheimer patients and 52 controls. In addition, post-mortem serum cortisol of 17 subjects from the Alzheimer group and nine from the control group were measured. The Alzheimer patients were subdivided according to their degree of dementia, as scored on the Reisberg Scale, before their death. All groups were further analyzed for the effect of morphine treatment, as well as for the effects of the confounding factors like age, gender, time, and season of death. Alzheimer patients had significantly higher cortisol levels than controls, both in CSF (mean (nmol/ l) 7 SEM: 482 7 32 vs 285 7 30, respectively, po0.001) and in serum (2854 7 279 vs 1533 7 395, p ¼ 0.011). Mean CSF cortisol level of the severely demented Alzheimer group was even significantly higher than that of mildly demented group (508 7 35 vs 225 7 65, p ¼ 0.024) and controls (po0.001). Cortisol levels correlated positively with the degree of dementia in the Alzheimer group (r ¼ 0.236, p ¼ 0.035). High-dose morphine did not cause a suppression of cortisol rise, neither in controls nor in Alzheimer patients. Our results indicate that the extreme elevations of cortisol levels during dying are rather due to the organic stress of the organism than to psychological stress of the patient, and is not suppressed by high-dose morphine.

Terminal Care: The Last Weeks of Life

“…111 Interestingly, the stress of dying (as measured by postmortem cerebrospinal fluid [CSF] cortisol levels) is not suppressed by either high-dose opioids or the presence of dementia. 112 This finding suggests that it may be our ability to assess pain, rather than the pain itself, that declines during the terminal phase. The assessment of cognitively impaired patients has been studied extensively in dementia, but there remains significant debate on whether cognitive status influences pain perception.…”

Postmortem Urinary Cortisol Levels in Relation to the Cause of Death

“…Erkut et al [8] found a similar relationship for cortisol in postmortem cerebrospinal fluid of multiple sclerosis patients, and concluded that the elevation probably related to the stressful event of dying since the relative elevation corresponded to the increase of cortisol observed in blood or serum of critically ill patients. In a further postmortem study of Alzheimer patients, Erkut et al [1] investigated whether psychological or physiological stress was likely to be most important with regard to death-related stress; they found that the most severely demented patients actually displayed the highest stress response and that administration of morphine did not have any impact. Thus, it was concluded that physiological rather than psychological stress in the dying period was decisive for the cortisol stress response.…”

“…Finlayson et al [7] studied 15 infants and 20 adults who all died suddenly or accidently, and found that the cortisol concentrations in their postmortem blood did not significantly differ from the reference levels from living persons. However, Erkut et al [1,8] found very high postmortem cortisol levels in the serum and in cerebrospinal fluid of patients with Alzheimer's disease or multiple sclerosis; they concluded that these levels were of similar magnitude to those observed in critically ill patients, such as those with septic shock or massive bleeding. Additionally, there are several published case reports relating to adrenocortical diseases, showing low postmortem serum or urine cortisol levels measured in cases with adrenal insufficiency [9][10][11].…”

“…Except for in sudden deaths, the death process is likely to coincide with some degree of stress related to psychological and/or physical conditions, such as anxiety, pain, troubled breathing, and multiorgan failure [1]. Thus, stress marker measurement may be of interest in cases where the circumstances relating to death are unclear.…”

<b>Alterações em adrenais de cães relacionadas à morte súbita ou agônica:</b> análise morfométrica, histopatológica, imunoistoquímica e correlação com os níveis de adrenalina e noradrenalina na medula adrenal

“…O estresse causado pelas condições críticas que levam à morte do organismo pode ser gerado pelo desconforto físico da dor intensa, por ansiedade na iminência da morte ou pela falência dos órgãos e sistemas que resultam na deterioração das funções corporais, levando ao comprometimento irreversível da homeostase e eventualmente ao óbito (ERKUT et al, 2004). A resposta ao estresse gerado pela iminência do óbito apresenta um componente físico muito mais intenso do que a porção psicológica, não sendo afetado pelo estado de consciência do indivíduo (ERKUT et al, 2004).…”