Effects of midazolam and dexmedetomidine on inflammatory responses and gastric intramucosal pH to sepsis, in critically ill patients
*
lu
. Vatan
mEdirne, Turkey
* E-mail: dilmemis{at}mynet.com
Editor—Despite advances in supportive care, the mortality rate in patients with severe sepsis continues to exceed 30%. Sedation is an important part of the therapy of critically ill patients in ICU. Although midazolam and dexmedetomidine are used for sedation in the ICU, there are limited data on its effects on inflammatory responses and gastric intramucosal pH. We studied the effect of midazolam and dexmedetomidine on the inflammatory responses [tumour necrosis factor-
(TNF-), interleukin (IL)-1ß, and IL-6] and gastric intramucosal pH in critically ill patients receiving sedation. The Regional Committee on Medical Research Ethics approved the study, and written informed consent was obtained from the patients wherever possible, or from the next of kin. Critically ill patients with bacteriologically documented infections were included in the study if they met at least two of the criteria of sepsis, defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee.1 Exclusion criteria were known allergy to midazolam or dexmedetomidine, possible or confirmed pregnancy, haemodynamic instability, heart, liver and renal failure, and patients with known or suspected brain death. The acute physiology and chronic health evaluation (APACHE II) was employed to determine the initial severity of illness.
Patients were allocated randomly, using sealed envelopes, to receive either dexmedetomidine or midazolam infusion together with an alfentanil infusion for analgesia if required. Patients received a loading dose of 0.2 mg kg–1 midazolam (Dormicum, Roche Laboratories, France) i.v. over 10 min followed by a maintenance 0.1–0.5 mg kg–1 h–1 infusion (n = 20, Group M). Patients received a loading dose of dexmedetomidine (Precedex® 200 µg in 2 ml, Abbott, North Chigaco, USA) 1 µg kg–1 h–1 over 10 min followed by a maintenance 0.2–2.5 µg kg–1 h–1 (n = 20, Group D) into a vein over 24 h infusion. Alfentanil was infused at 0.25–1.0 µg kg–1 min–1 if analgesia was required. The level of sedation was measured and recorded hourly using the Ramsay sedation score, and patients were maintained at a Ramsay sedation score <2 by adjustment to the sedative regimen. No other sedative or analgesic agents were given.
A tonometer (TRIP NGS Catheter, Tonometrics, Worchester, MA, USA) was inserted via the nasogastric route before the bolus dose. The silicone balloon of the tonometer was filled with 2.5 ml 0.9% saline. After sufficient time for equilibration of PCO2 between the saline and the gastric lumen, anaerobic samples of the tonometer saline and of arterial blood were taken simultaneously and analysed with standard pH and blood-gas analysers. pHi was calculated by a modification of the Henderson–Hasselbalch equation.
Mean arterial pressure and heart rate were monitored continuously. All measurements were obtained at baseline (before start of the study) and were repeated at 24 h. Lactate, platelets, leucocytes, bilirubin, alanine aminotransferase, creatinine, and pHi were determined at the same times, as were TNF-, IL-1ß, and IL-6 levels. Venous blood was collected into a 10 ml sterile plain tube (without anticoagulant) before administration of any medications and stored at –20°C. Before assay, all samples were thawed to room temperature and mixed by gentle swirling or inversion. All sera were assayed on the same day to avoid interassay variation. TNF-, IL-1ß, and IL-6 levels were measured with a solid-phase, two-site chemiluminescent enzyme immunometric assay method (Immulite TNF- Immulite IL-1ß, and IL-6 Immulite; EURO/DPC, Llanberis, UK). The lowest detectable limits of IL-1ß, IL-6, and TNF- were 1.5, 5, and 1.7 pg ml–1, respectively. Group means were compared, using the Student's t-test if the variables had a normal distrubition and the Mann–Whitney U-test if they did not have a normal distrubition.
Five patients had septic shock on admission [3 (15%) in Group M and 2 (10%) in Group D] and died in the ICU. Baseline APACHE II [18.10 (5.7) and 20 (4.72), Groups M and D, respectively] was similar (P > 0.05). The alfentanil requirements were similar in the two groups. The median (range) dexmedetomidine infusion rate was 0.90 (0.48–1.1) µg kg–1 h–1 and midazolam infusion rate was 0.29 (0.18–0.4) mg kg–1 h–1. Sedation was similar in the two groups (P = 0.71). No side-effects were noted during or after administration of midazolam and dexmedetomidine infusion. There were no statistically significant differences between the groups during the study with respect to haemodynamic and biochemical measurements, or gastric intramucosal pH. There were significant decreases in TNF- [19.5 (5.8) vs 14.6 (4) pg ml–1], IL-1ß [6.29(2) vs 5 (0.30) pg ml–1], IL-6 [455.6 (338.4) vs (212.4) (198.3) pg ml–1], at 24 h in Group D (P < 0.05) (Table 1).
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Gastric intramucosal pH in experimental animals decreases as splanchnic perfusion decreases below the level where local oxygen transport can no longer sustain aerobic energy production. Intramucosal acidosis has been associated with a poor prognosis and the appearance of multi-organ failure in critically ill patients, even in the absence of systemic acidosis or hypotension. In our study, we did not find a change in gastric intramucosal pHi.
Midazolam is known to inhibit certain aspects of the immune function.2 It was suggested that benzodiazepines bind to specific receptors on macrophages and inhibit their capacity to produce IL-1, IL-6, and TNF-.3 Several studies have found that midazolam inhibits human neutrophil function and the activation of mast cells induced by TNF- in vitro and suppresses the expression of IL-6 mRNA in blood monoclear cells.4 In contrast, several investigators reported that midazolam did not alter lipopolysaccharide (LPS)-stimulated cytokine response in vitro.5 6 In our study, midazolam infusion did not affect cytokine production in septic patients.
Only a few reports have dealt with the effects of dexmedetomidine during endotoxemia and endotoxic shock. Several investigators have published reports on the effects of dexmedetomidine and 2-adrenergic receptors agonists on cytokines,7 and 2-agonists modulated LPS-induced TNF- production on macrophages.8 Taniguchi and colleagues9 demonstrated that dexmedetomidine has an inhibitory effect on cytokine responses to endotoxemia. These findings suggest that one of the mechanisms of anti-inflammatory effects of dexmedetomidine may be modulation of cytokine production by macrophages and monocytes. We found that the dexmedetomidine infusion decreased cytokine production in sepsis.
Critically ill patients in sepsis and septic shock suffer a high degree of stress because of pain and anxiety and organ specific responses to sepsis. An important objective in the management of these patients is to achieve an adequate level of sedation and analgesia. Our findings suggest that dexmedetomidine may prevent inflammatory effects in sepsis patients during sedation.
References
1 Members of The American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–74.[Web of Science][Medline]
2 Helmy SAK and Al-Attiyah RJ. (2001) The immunomodulatory effects of prolonged intravenous infusion of propofol versus midazolam in critically ill surgical patients. Anaesthesia 56:4–8.[CrossRef][Web of Science][Medline]
3 Zavala F, Taupin V, Descamps-Latscha B. (1990) In vivo treatment with benzodiazepines inhibits murine phagocyte oxidative metabolism and production of interleukin-1, tumor necrosis factor and interleukin-6. J Pharmacol Exp Ther 255:442–50.
4 Nishina K, Akamatsu H, Mikawa K, et al. (1998) The inhibitory effects of thiopental, midazolam, and ketamine on human neutrophil functions. Anesth Analg 86:159–65.[Abstract]
5 Larsen B, Hoff G, Wilhelm W, et al. (1998) Effect of intravenous anesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human whole blood. Anesthesiology 89:1218–27.[CrossRef][Web of Science][Medline]
6 Takaono M, Yogosawa T, Okawa-Takatsuji M, Aotsuka S. (2002) Effects of intravenous anesthetics on interleukin (IL)-6 and IL-10 production by lipopolysaccharide-stimulated mononuclear cells from healthy volunteers. Acta Anaesthesiol Scand 46:176–9.[CrossRef][Web of Science][Medline]
7 Straub RH, Herrmann M, Berkmiller G, et al. (1997) Neuronal regulation of interleukin 6 secretion in murine spleen: adrenergic and opioidergic control. J Neurochem 68:1633–9.[Web of Science][Medline]
8 Szelenyi J, Kiss JP, Vizi ES. (2000) Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-alpha production by alpha2- and beta-adrenoceptors in mice. J Neuroimmunol 103:34–40.[CrossRef][Web of Science][Medline]
9 Taniguchi T, Kidani Y, Kanakura H, et al. (2004) Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med 32:1322–6.[CrossRef][Web of Science][Medline]
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