The immune side-effects of drugs commonly used in intensive care are summarized in T,albJ.§,,2..
Table 2 Immune side-effects of drugs commonly used in intensive care
The importance of the immune side-effects of drugs used regularly in intensive care was highlighted by a retrospective study of 428 trauma patients ( Watt and
Ledingham 1984). It showed an increase in mortality from around 25 per cent to 47 per cent associated with the introduction of etomidate for sedation. When etomidate was discontinued, the mortality of this group of patients returned to 25 per cent. Subsequently, etomidate was found to inhibit basal cortisol production and abolish the stress response. This report has salutary lessons: first, drugs that are used routinely may significantly affect outcome by immune modulation; second, ongoing auditing is imperative so that changing responses to treatment in individual units can be monitored.
Most drugs, apart from those used specifically to affect the immune response, have not been extensively studied for their immune effects. Drugs may have several contradictory effects at different points in the immune process.
The effects of modifying the stress response are confusing. While chronic blockade of cortisol release proved disadvantageous to outcome in the trauma patients given etomidate, there is believed to be some benefit in blocking the stress response during surgery. In fact, the postoperative rise in plasma cortisol concentrations has a destructive effect on some immune cells. Natural killer cell activity may be depressed following surgery under neuroleptanesthesia but not under epidural anesthesia. This may be due to the absence of a stress response in the epidural group.
Sedative drugs are used continuously for a prolonged period of time and so any depressant effect on immune function may have a significant effect on patient outcome. Morphine and midazolam are two of the sedative drugs most commonly used in the intensive care unit.
Midazolam appears to have a beneficial effect on immune function. It attenuates the rise in ACTH seen after surgery in experimental animals, inhibits the resulting fall in T-cell populations, and has no effect on neutrophil polarization.
Opioids inhibit the activity of natural killer cells in animals and humans, downregulate expression of human MHC class II (HLA-DR), increase levels of tumor necrosis factor-a and IL-8, and then increase anti-inflammatory cytokines (IL-10, IL-1ra, and tumor necrosis factor soluble receptors).
Propofol increases the production of tumor necrosis factor-a, IL-1a, and interferon-d, reduces neutrophil polarization and chemotaxis, inhibits neutrophil respiratory burst activity, inhibits proliferation of B lymphocytes in the critically ill, decreases the total number of T lymphocytes, memory T lymphocytes and B lymphocytes in healthy patients, and increases the number of helper T cells.
Thiopental (thiopentone) depresses neutrophil activity. Long-term high-dose thiopental infusion used for head injury and status epilepticus may be associated with an increased susceptibility to bacterial pneumonia.
Epinephrine (adrenaline) increases natural killer cell numbers, alters T-cell population ratios, and inhibits mitogen-induced proliferation of lymphocytes. In vitro, it inhibits human monocyte adhesion; this effect can be blocked by propranolol and is believed to be mediated by cAMP since it can be mimicked by cAMP analogs.
Dobutamine increases natural killer cell number and activity and increases lymphocyte numbers.
Isoprotenerol (isoprenaline) inhibits the production of tumor necrosis factor-a in vitro but has no effect on IL-1b.
Dopamine in vitro produces an immediate and transitory decrease in T-cell proliferative response. This also occurs following hypophysectomy and with the use of other dopamine agonists such as bromocryptine. Animal studies have shown that this affects outcome. Dopamine can be blocked with dopamine antagonists such as metoclopramide or haloperidol. Dopamine antagonists also reverse the immunosuppressive effects of cyclosporine and steroids.
Phosphodiesterase inhibitors include methylxanthines, theophylline, milrinone, amrinone, pentoxifylline, and dipyridamole. Each has different effects on the immune response; however, all increase intracellular cAMP, which inhibits the release and action of proinflammatory cytokines. Pentoxifylline and milrinone decrease the production of tumor necrosis factor-a. Pentoxifylline also inhibits neutrophil adhesion.
Diltiazem restores macrophage antigen presentation function and IL-1 expression in hemorrhaged animals.
Separation of the direct effects of alcohol on immune function from the effects of poor nutrition and liver dysfunction is difficult. However, acute and chronic alcohol consumption are both associated with decreased phagocytic activity, decreased opsonization, and depressed cellular immunity. Impairment in cellular immunity is aggravated by malnourishment. With cirrhosis, further defects in the immune system occur. Some of the direct effects of alcohol are in vitro depression of monocyte function, including antigen presentation and cytokine production, increasing activity and number of natural killer cells, which are implicated in hepatic damage, and decreasing number of T cells.
H2 blockers enhance immune function, inhibit suppressor T-cell function via H 2 receptors, and increase IL-2 production, cell-mediated cytotoxicity, and lymphocyte viability.
Nitric oxide (NO) is a central participant in both the non-specific and specific immune response. Together with cytokines, NO is produced by stimulated macrophages. It kills many microbes and inhibits their replication, and increases lymphocyte proliferation. The significance of these effects with respect to attempts to inhibit NO in sepsis are as yet unknown.
Various antibiotics have been tested for their suppression of lymphocyte numbers at therapeutic concentrations. Minocycline and oxytetracycline are the most suppressive, followed by chloramphenicol, clindamycin, and tetracycline. Penicillin, carbenicillin, and cephalothin have no effect. Gentamicin stimulates the response.
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