Anesthesiology 1

Perioperative Medicine: Efficacy, Safety and Outcome

Principal investigators

Prof. dr. A. Dahan, dr. L.J. Teppema, dr. R. Stienstra, dr. B. Veering, dr. J. Vuyk and Prof. Dr. J.W. van Kleef.

Aim and focus

Pharmacological interventions from anesthesia and pain treatment have a major impact on the (patho)-physiology of the individual patient. Our research is aimed at pharmacological, physiological and genetic studies of the perioperative patient and the chronic pain patient by studying the influence of surgery, pain/stress, anesthesia and pain relief on patient outcome and safety. The focus of studies is on the optimization of anesthetic and pain medication while minimizing unwanted drug and pain/stress induced effects.

Position in international context

The research is original and uses state-of-the-art techniques. It is well positioned within the internationally operating research groups on anesthesia, pain and ventilatory control. Currently there are active co-operations and contacts with several international and national research groups, such as in the US and Canada (dr. B. Kest, CUNY; Prof. J. Mogill, McGill, Prof. E. Swenson, University of Washington), Germany (Profs. Kiwull and Kiwull-Schöne, Bochum), the UK (dr. G. Drummond, Edinburgh; Prof. P. Robbins, Oxford; Prof. M. Maze and Prof. N. Franks, Imperial College; dr. G. Balanos, Birmingham) and the Netherlands (Prof. van Kleef, University Hospital Maastricht).

Content/highlights/achievements

There are several lines of research within programme 1.01.01:

1. Pharmacokinetic/pharmacodynamic modelling of intended effects and side effects of opioids. Studies are performed in rodents, human volunteers (phase I-II) and clinical patients (phase II-III), with important results on new opioids (e.g., morphine-6-glucuronide) and the reversibility of opioid-side effects using naloxone. Population PK/PD/PG (pharmacogenetics) analysis techniques are applied. Since our experimental set-up is unique (for example, it allows the simultaneous assessment of opioid effect and side effect, such as opioid-induced respiratory depression), this line of research is able to generate generous funding from the pharmaceutical industries.  

2. (Patho)-physiology of the control of breathing. This very successful line of research is aimed at the study of oxygen-sensing at the carotid bodies and the pulmonary vascular bed. Recently the plastic effects of carotid body resection on brainstem respiratory functions were observed for the first time in humans.

3. Acute and chronic pain. The effectiveness of analgesic and local anesthetic regimens is tested along preclinical and clinical lines. In preclinical studies opioid analgesia and hyperalgesia is studied in rodents and human volunteers. In clinical studies analgesic treatment for postoperative acute pain and chronic pain (e.g., chronic pain in CRPS type 1 patients) is studied. Part of this work is funded by TREND (a national cooperative consortium studying CRPS-1).

Future themes

Perioperative outcome.

In cooperation with the ICU we will start a longitudinal study on the effect of hyperglycemia and its treatment in the perioperative phase on postoperative outcome. 

Cohesion within LUMC

The research is performed in cooperation with various groups in the LUMC, such as:

The departments of Otorhinolaryngology and Surgery (2), the department of Human Genetics (1 and 3), the department of Toxicology and Clinical Pharmacy (1), the department of Neurology (3), and the department of Internal Medicine (2), as well as with groups within the Leiden University (LACDR and CHDR) and the Technical University of Delft.

Key publications

Dahan A, Nieuwenhuijs D, Teppema LJ. Plasticity of Central Chemoreceptors: Effect of Bilateral Carotid Body Resection on Central CO₂ Sensitivity. PLoS Medicine 2007; 4(7): e239. doi:10.1371/journal.pmed.0040239.
IF 13.8

 Teppema LJ,  Balanos GM,  Steinback CD,  Brown AD,  Foster GE,  Duff HJ,  Leigh R,  Poulin MJ. Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Resp. Crit Care Med 2007; 175: 277-281
IF 9.0

Yassen A, Olofsen E, Romberg R, Sarton E, Teppema L, Danhof M, Dahan A. Mechanism based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin. Pharmacol Ther 2007, 81: 50-58.
IF 8.1

van Dorp E, Yassen A, Sarton E, Romberg R, Olofsen E, Teppema L, Danhof M, Dahan A. Naloxone-reversal of buprenorphine-induced respiratory depression. Anesthesiology 2006, 105: 51-57.
IF 4.2

Mogil J, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR, Romberg RR, Bijl H, Sarton EY, Fillingim RB, Dahan A. Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. J Med Genet 2005, 42: 583-587.
IF 5.1

Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, Tephly T, Dahan A, Beijnen JH, Borst P. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and decreased antinociception by morphine-6-glucuronide. Proc Natl Acad Sci USA, 2005; 102: 7274-7279.
IF 9.6

Lichtenbelt BJ. Mertens M, Vuyk J. Strategies to optimise propofol-opioid anaesthesia. Clin. Pharmacokinet 2004; 43: 577-593.
IMP FACTOR 4.1

Leeda M, Stienstra R, Arbous M, Verschure MJM, Dahan A, Veering BTh, van Kleef JW, Burm AGL. The Epidural ‘Top-Up’: Predictors of Increase of Sensory Blockade. Anesthesiology 2002; 96: 1310-1314.
IF 4.2

Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D, Burm A, Teppema L, Dahan A: Sex differences in morphine analgesia: An experimental study in healthy volunteers. Anesthesiology 2000; 93: 1245-1254.
IF 4.2

Teppema L, Dahan A. Acetazolamide and breathing: Does a clinical dose alter peripheral and central CO₂ sensitivity? Am J Resp. Crit Care Med 1999; 160: 1592-1597.
IF 9.0