anesthesiologie Nederlands tijdschrift voor volume 23, juni 2011

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anesthesiologie volume 23, juni 2011

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• Take home messages from 2010: The Leiden perspective S. Koster, M. Boom, A. Morariu, A. de Roode, L. Aarts, A. Dahan • Infant with Pierre Robin Sequence: progression form Cormack and Lehane grade I to grade III in four months R.C. Mebus, J.H.A.M. Megens • Anesthetic management in Bartter syndrome J.J.M.G. Theunissen, D.G. Snijdelaar, G.-J. Scheffer • BAV, TAA and TEE V. Gerling, W. Buhre, L. van Herwerden • Acute Porphyria: Pandora’s box in perioperative care K. Ariese, T.A. Brans, M.J. van den Elsen, S.A. Loer, C. Boer • Conflict of interest P.J.A. van der Starre, H.J.H.M. Lemmens

Dr. M. Klimek, hoofdredacteur Dr. C. Boer, plaatsvervangend hoofdredacteur

Officiële uitgave van de Nederlandse Vereniging voor Anesthesiologie

Zo vader, zo zoon • Effectieve pijnstilling voor volwassenen van elke leeftijd1 • Breed toepasbaar1, zoals bij lage rugpijn* • Geen specifieke cardiovasculaire & gastro-intestinale complicaties1 • Uitstekend te combineren met lage dosering NSAID 2-4 *voor de symptomatische behandeling van matige tot ernstige pijn

Zeker Zaldiar

ZLD-ADV-20110104-01

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OOK ALS BRUISTABLET

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nederlands tijdschrift voor anesthesiologie juni ’11

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Inhoud Nederlands tijdschrift voor

anesthesiologie volume 23 Nummer 3 juni 2011

Coverbeeld: Dimitry de Bruin

editorial

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Topartikelen M. Klimek

review

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Take home messages from 2010: The Leiden perspective S. Koster, M. Boom, A. Morariu, A. de Roode, L. Aarts, A. Dahan

case report

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Infant with Pierre Robin Sequence: progression form Cormack and Lehane grade I to grade III in four months R.C. Mebus, J.H.A.M. Megens

case report

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Anesthetic management in Bartter syndrome J.J.M.G. Theunissen, D.G. Snijdelaar, G.-J. Scheffer

case report

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BAV, TAA and TEE V. Gerling, W. Buhre, L. van Herwerden

review

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Acute Porphyria Pandora’s box in perioperative care K. Ariese, T.A. Brans, M.J. van den Elsen, S.A. Loer, C. Boer

ingezonden

Conflict of interest P.J.A. van der Starre, H.J.H.M. Lemmens

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Bij perifere neuropathische pijn

maximaal maxima 1 uur aanbrengen 3 maanden ma pijnverlichting1-3

Zie voor de verkorte productinformatie elders in dit blad

juni ’11 nederlands tijdschrift voor anesthesiologie

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Colofon Het Nederlands Tijdschrift voor Anes thesiologie is het officiële orgaan van de Nederlandse Vereniging voor Anesthe siologie. Het stelt zich ten doel om door middel van publicatie van overzichts artikelen, klinische en laboratorium studies en casuïstiek, de verspreiding van kennis betreffende de anesthesi ologie en gerelateerde vakgebieden te bevorderen. REDACTIE

Kernredacteuren: Dr. C. Boer, Prof. Dr. A. Dahan, Dr. H. van Dongen, Dr. H.G.D. Hendriks, Prof. Dr. S. de Hert, Dr. M. Klimek, Prof. Dr. J. Knape, Prof. Dr. M.A.E. Marcus, Prof. Dr. G. Scheffer. Ondersteunend redacteuren: Drs. M. van der Beek, Dr. P. Bruins, Drs. G.P.G. Filippini-de Moor, Dr. D. Gommers, Dr. J.P. Hering, Prof. Dr. M. Hollmann, Dr. W. Klei, Dr. A. Koopman, Drs. M. Lance, Prof. Dr. S.A. Loer, Dr. S. Schiere, Dr. B. in het Veld, Dr. K. Vissers, Dr. J.K.G. Wietasch. Secretaresse: mw. W. van Engelshoven Voor informatie over adverteren en het reserveren van advertentieruimte in het Nederlands Tijdschrift voor Anesthesiologie: Mw W. van Engelshoven e-mail: [email protected]

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OPLAGE 2.500 exemplaren, 5x per jaar Het NTvA wordt uitsluitend toegezonden aan leden van de NVA. Adreswijzigingen: Nederlandse Vereniging voor Anesthesiologie, Postbus 20063, 3502 LB Utrecht, tel. 030-2823385, fax 030-2823856, e-mail [email protected]

PRODUCTIE

Bladcoördinatie: Drs. Thomas Eldering (023-5259332) Ontwerp: Dimitry de Bruin Eindredactie: Monique de Mijttenaere

AUTEURSRECHT EN AANSPRAKELIJKHEID

© De Stichting tot Beheer van het Nederlands Tijdschrift voor Anesthesiologie 2009. Nederlands Tijdschrift voor Anesthesiologie® is een wettig gedeponeerd woordmerk van de Nederlandse Vereniging voor Anesthesiologie. Alle rechten voorbehouden. Niets uit deze uitgave mag worden verveelvoudigd, opgeslagen in een geautomatiseerd gegevensbestand of openbaar gemaakt, in enige vorm of op enige wijzen, hetzij elektronisch, mechanisch, door fotokopieën, opnamen of enige andere manier, zonder voorafgaande schriftelijke toestemming.

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editorial M. Klimek Hoofdredacteur

Topartikelen

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eachte lezer, Wat zijn de kenmerken van een echt topartikel? Dit vraag ik mij af, terwijl wij in deze uitgave van het NTvA onder andere de conclusies publiceren, die door collega’s uit het LUMC getrokken werden uit een selectie artikelen uit 2010, die zij als bijzonder belangrijk hebben beoordeeld. Tegelijkertijd moet de redactieraad bedenken, welk artikel wij op de aankomende Anesthesiologendagen als beste publicatie uit het NTvA van 2010 zullen onderscheiden. Originaliteit van het onderwerp, inspiratie, zuiverheid van de methodiek, innovatie, toepasbaarheid van de resultaten, integriteit van de discussie… Er vallen veel criteria te bedenken, die een artikel goed maken, en de uiteindelijke keuze blijft toch altijd wat subjectief. Gemakkelijker is het om te definiëren wat een artikel slecht maakt. Ook hier had 2010 een indrukwekkend voorbeeld: op 28 oktober 2010 werd het artikel “Cardiopulmonary Bypass Priming Using a High Dose of a Balanced Hydroxyethyl Starch Versus an AlbuminBased Priming strategy” door Joachim Boldt et al. (Anesthesia & Analgesia 2009;109: 17521762) officieel teruggetrokken. Na uitgebreid onderzoek concludeerde de hoofdredactie, dat het beschreven onderzoek waarschijnlijk nooit heeft plaatsgevonden en het artikel volledig uit de duim gezogen is. Hierop aansluitend werd uitgebreid onderzoek naar overige publicaties van dezelfde auteur gedaan, en vond men uiteindelijk 89 artikelen waar vraagtekens werden geplaatst betreffende de mogelijk ontbrekende goedkeuring door de ethische commissie en/of de correctheid van het beschreven onderzoek. Anesthesia & Analgesia heeft naar aanleiding hiervan op 28 februari jongstleden nog 22 andere artikelen van Joachim Boldt et al. uit de jaren 1999-2009 teruggetrokken. Laat mij duidelijk zijn: er is geen plek voor wetenschappelijke fraude of onethisch (en dat betekent in geval van twijfel ook: niet door de hiervoor in het leven geroepen ethische commissies goedgekeurd) onderzoek. Gezien de in deze casus ook nog bestaande belangenconflicten ten aanzien van de producenten van infuusvloeistoffen enerzijds en de invloed, die deze artikelen op diverse richtlijnen over het vochtbeleid anderzijds hebben gehad, is

de schade dramatisch – overigens ook voor de auteur zelf. De vraag “Waarom?” kunnen wij niet sluitend beantwoorden, maar het ligt voor de hand, dat topartikelen ook tot invloed, macht, gratificaties en andere egostrelende situaties kunnen leiden en dat blijkbaar de drempel om hiervoor ook foute dingen te doen niet voor iedereen even hoog ligt. Aan de andere kant, en ook dit vraagt aandacht, is het zich nu afspelende academische, mogelijk financiële en zeker persoonlijke drama voor de betrapte fraudeur en de mensen achter en onder hem een existentieel bedreigende situatie. Zo bedreigend, dat sommige deze druk niet kunnen weerstaan en de steun van anderen – en dus ook van ons - nodig hebben. Het is gemakkelijk, om in het koor van (voor-) veroordelingen mee te zingen – en nog eens: fout is fout, ik kan het niet mooier maken – maar: na de straf bestaat ook een recht op rehabilitatie en resocialisatie! Het NTvA kent in de auteursrichtlijnen tot nu toe geen clausules met betrekking tot mogelijke belangenverstrengelingen. Naar aanleiding van de pro/con-discussie over succinylcholine werden wij door alerte lezers erop geattendeerd, dat een dergelijke clausule wenselijk zou zijn. Wij nemen deze suggestie graag op en zullen tijdens de volgende redactievergadering hierover beslissen. Moeten wij dus voor deze achtergrond nog topartikelen binnen en buiten het NTvA bekronen en misschien een systeem onderhouden, dat fraude en/of belangenverstrengelingen en/of onethisch handelen begunstigt? Ik denk van wel, want er zit tussen de grote groep van eerlijke wetenschappers die met veel transpiratie en inspiratie op zuivere manier hun resultaten op papier zetten, die nuttig en soms zelfs nodig zijn voor onze patiënten en onszelf, slechts een gering aantal fraudeurs. En net zoals deze fraudeurs hun ontmaskering verdienen, verdienen de harde en eerlijke wetenschappers het ook om in het zonnetje gezet te worden. Vandaar dat ik blij ben dat wij u ook met deze uitgave van het NTvA weer een bloemlezing van artikelen mogen aanbieden, die u ook als hopelijk nuttig ervaart. Ik wens u Top-Leesplezier! Dr. Markus Klimek, hoofdredacteur

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review

Take home messages from 2010

The Leiden perspective

Department of Anesthesiology, Leiden University Medical Center contactinformation Albert Dahan, MD PhD Professor of Anesthesiology Leiden University Medical Center Albinusdreef 2 2333 ZA Leiden The Netherlands

Stephanie Koster Merel Boom Aurora Morariu Annemiek de Roode Leon Aarts Albert Dahan

2010 was again an important year for research with many fascinating and important scientific discoveries. Analogous to our previous publication in December 2008, we present a series of papers on 5 different topics that we consider of high interest to the anesthesiologists and were published in 2010. In this article we present a series of publications covering 4 distinct topics: Pain, ketamineuse in depression, posttraumatic stress and airway management. Some of the topics go beyond our everyday practice but they broaden our scope and are relevant to all of us!

1. Pain • Mechanisms of association between obesity and chronic pain in the elderly, by Ray et al., Pain 2010, published online ahead of print. • Pain inhibition is deficient in chronic widespread pain but normal in major depressive disorder, by Normand et al., J Clin Psychiatry 2010, published online ahead of print. • Viewing pictures of a romantic partner reduces experimental pain: Involvement of neural reward systems, by Younger et al., PLoS ONE 5(10): e13309. doi:10.1371/ journal. pone.0013309. Chronic pain affects an increasing number of people worldwide. In parallel, the number of papers that address chronic pain increases steadily. Some of these studies give us a further insight in the epidemiology of pain and mechanisms involved in the chronification of pain. Chronic pain is more common in the elderly and Ray et al. studied the relationship between obesity and

chronic pain in cohort of more than 400 individuals, the so called ‘Einstein Aging Study’, living in the Bronx, NY, and with age > 70 years. Fifty-two percent of the people tested had chronic pain, 46% were obese. Of all parameters tested, central obesity (as defined by the waist circumference) was the most important and consistent risk factor for chronic pain. A relationship between pain and food has been made before, for example hedonistic food intake is accompanied by analgesia (See J Neurosci 2009; 29: 13053-62). We remain unknown whether the link between obesity and chronic pain is a causative one. The study does however set us on the track of programs focusing on lifestyle weight management as already a modest weight loss can results in significant pain relief. One mechanism through which our body modulates pain perception is endogenous inhibition of pain. Top-down serotonergic, opioidergic and adrenergic neuronal pathways are involved in this system. Normand et al. showed that endogenous inhibition is deficient in patients with chronic pain but per-

sists in patients with mood disorders. Younger et al. tested pain perception in individuals in the first nine months of a new, romantic relationship and observed that viewing a picture of the romantic partner reduced pain perception significantly due to activation of brain centers involved in reward. Again we remain uniformed whether the link between pain and dysfunctional endogenous inhibition and reward systems is causative or secondary (for example, a result of chronic pain). However, these studies open the road to new treatment aimed at pharmacological and nonpharmacological restoration of endogenous pain pathways.

2. Ketamine • mTOR dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists, by Li et al., Science 2010; 329: 959-964. Ketamine has started its 2nd life as analgesic for treatment of chronic pain. However, there is an even more impressive new role for ketamine in the treatment of depression in patients resistant


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to traditional therapy. The effect of ketamine is rapid (within hours) in contrast to commonly used anti-depressant therapy that requires weeks to months of therapy before mood improvement sets in. Li et al. studied the effect of ketamine in rodents and observed that 10-mg/kg ketamine activates the mTOR (mammalian target of rapamycine) signaling pathway. Other therapies, including electroconvulsive therapy (ECT) had no effect on mTOR. Blockade of mTOR leads to the inability of ketamine and traditional antidepressant to have an effect in various animal models of depression. mTOR activation results in increased synaptic activity (including serotonergic signaling) and new synapse formation in the prefrontal cortex. These effects are opposite the effects of stress on the brain. We see this paper as an important first step in further understanding the complex actions of the ‘tiger’ ketamine (Anesthesiology 2010; 113: 678-86). Possibly mTOR plays an evenly important role in the production of rapid pain relief following ketamine treatment of chronic pain patients.

3. Posttraumatic stress • Morphine use after combat injury in Iraq and post-traumatic stress disorder, by Holbrook et al., N Eng J Med 2010; 362: 110-117. • Posttraumatic stress disorder in aware patients from the B-aware trial. Anesthesia & Analgesia 2010 110: 823-828. Posttraumatic stress disorder (PTSD) can develop after exposure to any event that results in stress and psychological trauma. It is a mental disorder with a clearly identified cause and onset. In humans it takes up to 6 hours before a memory event is permanently stored and/or imprinted. Furthermore a traumatic event is often replayed for variable periods of time causing recurrent sympathetic arousal and further memory consolidation. Early studies indicated a protective effect of morphine on PTSD in children after burn injuries (J Am Acad Child Adolesc Psychiatry 2001; 40: 915-21). A protective role of morphine on PTSD may either be via reduction of pain (pain has been associated with PTSD) or via a protective function on PTSD per se. The latter process may occur by inhibition of nor-

adrenaline release in the amygdala and locus coeruleus by opioids. Holbrook and colleagues studies almost 700 injured soldiers injured during combat in Operation Iraqi Freedom in 20042006. Some soldiers were treated with morphine during early resuscitation and some developed PTSD. Among the patients in whom PTSD developed, 61% received morphine; among those in whom PTSD did not develop, 76% received morphine (odds ratio, 0.47; P < 0.001). This suggests a protective role for the use of morphine in the prevention of PTSD. Closer to our own practice, PTSD is common and persistent in confirmed awareness patients as studied in the BAware Trial by Leslie et al. 71% of confirmed awareness patients and 12% of controls developed PTSD (odds ratio 13.3, P = 0.02). The onset of PTSD was 14 days postoperatively and the duration more than 4 years. Evidently, prevention of awareness is a first but prevention of PTSD is evenly important. Taken into account the lessons learned in Iraq, it may well be that supportive measures in the first hours postoperatively should include an iv bolus dose of morphine (5-10 mg).

4. Airway management • Effects of preoxygenation on desaturation time during hemorrhagic shock in pigs, by Pehböck et al., Anesthesiology 2010; 113: 593-599. Patients in hemorrhagic shock often require emergency airway management by rapid sequence induction to secure the airway and provide adequate oxygenation and ventilation. This type of induction exposes the patient to a period of apnea before an airway can be established. Oxygen desaturation to critical hypoxemia (peripheral HbO2 saturation < 70%) occurs rapidly in specific circumstances. A difficult airway or difficult mask ventilation (suspected cases are obesity, pregnancy, regurgitation, criticall ill patients) may increase the risk and onset of hypoxemia. Adequate preoxygenation before rapid sequence induction is paramount to avoid critical hypoxemia because this will lead to more time to intubate. Pre-oxygenation has been examined extensively and recommendations for its duration vary between 2 and 7 min (Anaesthesia 2001;56: 1090-1115).

It is more difficult to increase oxygen saturation in critically ill patients and patients with traumatic injuries due to increased oxygen consumption, blood loss, stress, hypoventilation, and inadequate lung perfusion. The determinants of desaturation are poorly studied, but one mechanism could rely on traumatic blood loss and shock. In a porcine shock model, Pehböck et al. studied the hypothesis that increasing levels of hemorrhagic shock, varying levels of FiO2 for preoxygenation and fluid resuscitation significantly affect the time window until critical desaturation occurs. Pigs were randomly allocated to receive no fluid or fluid resuscitation. At each shock level, apnea experiments were performed after 5 min of preoxygenation at 21, 50, or 100% FiO2. It was repeated at three hemorrhagic levels: 15 ml/kg, 30 ml/kg and 45 ml/kg blood loss. After preoxygenation, ventilation was discontinued and the time to peripheral oxygen saturation of 70% or less was measured. During normovolemia, peripheral oxygen desaturation to less than 70% occurred after 33 ± 7 s (Fio2 = 0.21, mean ± SD), 89 ± 12 s (Fio2 = 0.5), and 165 ± 22 s (Fio2 = 1.0; P < 0.001). During increasing blood loss, peripheral oxygen desaturation to Spo2 less than 70% occurred significantly (P < 0.001) faster compared with normovolemia, but no effect of fluid resuscitation was observed. With 45 ml/kg blood loss, peripheral oxygen desaturation to less than 70% occurred after approximately 15 (Fio2 = 0.21) to 65 (Fio2 = 0.5) to 140 s (Fio2 = 1.0). Fio2 and the level of blood loss, but not fluid resuscitation, influence the rate of apneic desaturation. During airway management (in emergent and non-emergent situations) preoxygenation with 100% oxygen is the best method to optimize intubation conditions. Although we are specialized in airway management, it remains very helpfull and necessary to know how to best avoid critical hypoxemia. Mortality increases rapidly when the patient desaturates to levels below 70% for more than 2 min (J Trauma 2004; 57: 1-8). The data of Pehböck et al. is important as it exemplifies the need for adequate oxygenation with 100% O2 during airway management in emergency (and other) circumstances.


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case report

Infant with Pierre Robin Sequence: progression from Cormack and Lehane grade I to grade III in four months

1 Department of Anesthesiology, Intensive Care and Pain Management, St. Antonius Hospital, Nieuwegein, The Netherlands 2 Department of Peri-operative Care & Emergency Medicine, Wilhelmina Children’s Hospital University Medical Centre Utrecht, Utrecht, The Netherlands contactinformation Ralph C. Mebus Department of Anesthesiology, Intensive Care and Pain Management St. Antonius Hospital Koekoekslaan1 3435 CM Nieuwegein The Netherlands T +31 (0)88 3203000 Email [email protected]

R.C. Mebus, MD 1 J.H.A.M. Megens, MD 2

In patients with Pierre Robin Sequence (PRS) management of the airway can be extremely difficult due to the micro- and retrognathia. Most anesthesiologists are well aware of the difficulties that may arise at induction of general anesthesia in such patients. We present the case of an infant in which management of the airway was difficult although previous general anaesthetic and airway management, a few months earlier, were uneventful.

Case report An eleven month old female patient, weighing eleven kilogram, known with Pierre Robin Sequence was scheduled to undergo surgery. Her medical history, reported no incidents of dyspnoea or discoloration due to airway obstruction; she was seeing a speech specialist because of feeding difficulties. Physical examination was unremarkable except for the microand retrognathia with submucosal cleft palate and bilateral clubfeet. At the age of seven months the patient underwent an achilles tenotomy; a part of the Ponseti clubfoot treatment. The previous anesthetic record revealed no difficulties maintaining the airway: mask ventilation could be performed by one person, tracheal intubation was not necessary on this occasion and a laryngeal mask size 1½ was correctly positioned. The patient was also scheduled for cleft palate correction a few months later. Therefore, laryngoscopy was performed to estimate intubation difficulties in the near future; the posterior part of the vocal cords was visualized with laryngoscope using mild external pressure to the larynx.

At the age of eleven months, the patient was scheduled to undergo surgical correction of a cleft palate and insertion of ventilation tubes for middle ear drainage. The operating team was informed that management of the airway on a previous occasion was without difficulty. The operating room was prepared and laryngeal masks of various sizes were at hand, the difficult intubation trolley was readily available. Anesthesia was induced with Sevoflurane in oxygen by facemask; spontaneous ventilation was unobstructed and mask ventilation could easily be performed by one person. Monitoring included pulse oximetry, electrocardiogram and capnography. After placement of a peripheral intravenous cannula, Sufentanil 2 mg and Atracurium 5 mg were administered. At the first attempt of tracheal intubation only a small edge of the epiglottis was visible, the vocal cords could not be visualized. Two intubation attempts ended in the esophagus. A laryngeal mask airway (LMA) was inserted and tracheal intubation through the LMA was attempted once, but was unsuccessful. Oral intubation using a fiber-

scope was attempted supported by jaw thrust. The fiberscope could easily be advanced into the trachea and a size 4.0 reinforced - non cuffed - tube (Mallinckrodt® Safety-Flex™) was correctly positioned in the trachea, as was verified by auscultation and capnography. During the intubation attempts oxygenation remained adequate, oxygen saturation levels did not fall below 95%. Anesthesia continued with sevoflurane in oxygen and air, supplemented with sufentanil; acetaminophen 170 mg and morphine 1 mg was administered to treat postoperative pain. The surgical correction proceeded uneventful. The patient was extubated when fully awake and with return of airway reflexes. There were no postoperative anesthesia complications. The nature of the airway difficulty was documented in the medical record. The mother of the patient was notified of the problems that had arisen during anesthesia. She then revealed that the patient had developed six new teeth between the current and the previous anesthetic procedure.

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Discussion The Pierre Robin Sequence is characterized by the clinical triad of micrognathia, glossoptosis and a U-shaped cleft palate. It is estimated to affect approximately 1 in 8.500 births and can be isolated or in association with other congenital anomalies. The single initiating defect may be hypoplasia of the mandibula of the fetus before the 9th week, forcing the tongue to be positioned posterior and thereby impairing the posterior palatal shelves to grow over the tongue and meet in the midline for closure [1]. Much of the airway obstruction observed in patients with PRS occurs at the tongue base because of glossoptosis, but is in fact multifactorial in nature [2]. Children with PRS often need airway intervention; which can both be surgical and nonsurgical [3].

In patients with PRS, both mask ventilation and tracheal intubation can be extremely difficult; fiber optic intubation while the patient is awake is generally considered the most reliable airway management [4]. The uncooperative or pediatric patient may restrict the options for difficult airway management, particularly options that involve awake intubation. Airway management in the uncooperative or pediatric patient may require intubation attempts after induction of general anesthesia, as stated by the American Society of Anesthesiologists task force on management of the difficult airway [5]. In general patients with isolated PRS, the mandible may grow to approximately normal size so that the patient “grows out

of “ the airway obstruction because of expansion of the oral cavity [6]. Difficulty in airway management was not anticipated in this patient; a previous anesthetic and airway management was uneventful and as patients with PRS get older airway difficulties become less prominent because of the growth of the mandibula. Nevertheless, due to the development of six new teeth tracheal intubation was difficult in this patient. The interincisor distance was smaller with less room to manipulate the laryngoscope. In conclusion, previous uncomplicated airway management in patients with Pierre Robin Sequence does not vouch for a successful airway management in subsequent anesthetic, especially in children teething.

references 1. Facial defects as major feature. In Jones K.L., eds. Smith’s Recognizable patterns of Human Malformation, 5th ed. Philadelphia: Saunders 1997: 234. 2. Sher A.E., Shprintzen R.J., Thorpy M.J. Endoscopic observations of obstructive sleep anpea in children with anaomalous upper airways: predictieve and therapeutic value. Int J Ped Otorhinolaryngology 1986; 11: 135-146. 3. Meyer A.C., Lidsky M.E., Sampson D.E., Lander T.A., Liu M., Sidman J.D. Airway interventions in children with Pierre Robin Sequence. Otolaryngology – Head and Neck

Advertentie Surgery 2008; 138: 782–787. 4. Howardy-Hansen P., Bertelsen P. Fiberoptic bronchoscopic nasotracheal intubation of a neonate with Pierre Robin syndrome. Anaesthesia 1988; 43: 121-122. 5. Practice Guidelines for management of the difficult airway. An updated report by the American Society of Anesthesiologists task force on management of the difficult airway. Anesthesiology 2003; 98: 1269-77. 6. Nagozian C. The airway in patients with craniofacial abnormalities. Pediatric Anesthesia 2004; 14: 5359.

Referenties: 1. SmPC Instanyl® 50, 100, 200 µg/dosis, juli 2009 2. Christrup LL et al. Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: a randomized, double-blind, double-dummy, two-way, crossover study. Clin Ther 2008;30:469-481 3. Kress HG et al. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 mg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clin Ther 2009;31 4. Mercadante S et al. A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain – an open-label, randomised, crossover trial. Curr Med Res Opin 2009;25(11):2805-2815 Instanyl 50 microgram/dosis neusspray, oplossing. Instanyl 100 microgram/dosis neusspray, oplossing. Instanyl 200 microgram/dosis neusspray, oplossing. Kwalitatieve en kwantitatieve samenstelling: 1 ml oplossing bevat fentanylcitraat equivalent aan respectievelijk 500, 1000 en 2000 microgram fentanyl. 1 dosis (100 microliter) bevat respectievelijk 50, 100 en 200 microgram fentanyl. Farmaceutische vorm: Neusspray, oplossing. Heldere, kleurloze oplossing. Therapeutische indicaties: Instanyl is geïndiceerd voor de behandeling van doorbraakpijn bij volwassenen die al een onderhoudsbehandeling met opioïden ontvangen tegen chronische kankerpijn. Doorbraakpijn is een tijdelijke exacerbatie van pijn die optreedt bovenop een bestaande, aanhoudende pijn die reeds onder controle is. Patiënten die een onderhoudsbehandeling met opioïden ontvangen, gebruiken minstens 60 mg orale morfine per dag, minstens 25 microgram transdermale fentanyl per uur, minstens 30 mg oxycodon per dag, minstens 8 mg orale hydromorfon per dag of een equianalgetische dosis van een ander opioïd gedurende één week of langer. Dosering en wijze van toediening: De behandeling dient te worden ingesteld door en onder toezicht te blijven van een arts met ervaring in de behandeling van kankerpatiënten met opioïden. Voor verdere informatie, zie de volledige IB-tekst. Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel of voor één van de hulpstoffen. Gebruik bij opioïd-naïeve patiënten. Ernstige respiratoire depressie of ernstige obstructieve longaandoeningen. Eerdere faciale radiotherapie. Terugkerende epistaxisaanvallen. Bijzondere waarschuwingen en voorzorgen bij gebruik: Zoals bij alle krachtige opioïden kan er klinisch significante respiratoire depressie optreden bij gebruik van fentanyl en moeten patiënten geobserveerd worden op deze effecten. Patiënten met pijn die een chronische opioïdbehandeling ontvangen, ontwikkelen een tolerantie voor respiratoire depressie en dus is het risico op respiratoire depressie bij deze patiënten lager. Gelijktijdig gebruik van geneesmiddelen die het centrale zenuwstelsel onderdrukken kan het risico op respiratoire depressie verhogen. Bij patiënten met chronische obstructieve longaandoeningen kan fentanyl ernstigere bijwerkingen hebben. Bij deze patiënten kunnen opioïden de ademhalingsprikkel onderdrukken en de weerstand van de luchtwegen verhogen. Fentanyl dient met zorg te worden toegediend aan patiënten met matige tot ernstige lever- of nierfunctiestoornissen. De invloed van lever- en nierfunctiestoornissen op de farmacokinetiek van Instanyl is niet geëvalueerd; wanneer fentanyl echter intraveneus wordt toegediend, is de klaring gewijzigd als gevolg van lever- en nierfunctiestoornissen, veroorzaakt door veranderingen in metabole klaring en plasma-eiwitten. Fentanyl dient met zorg te worden gebruikt bij patiënten met tekenen van een verhoogde intracraniale druk, een verminderd bewustzijn of coma. Instanyl dient met zorg te worden gebruikt bij patiënten met een hersentumor of hoofdletsel. Fentanyl kan bradycardie veroorzaken. Fentanyl dient daarom met zorg te worden toegediend aan patiënten met bradyaritmie. Opioïden kunnen hypotonie veroorzaken, vooral bij patiënten met hypovolemie. Instanyl dient daarom met zorg te worden gebruikt bij patiënten met hypotonie en/of hypovolemie. Als de patiënt herhaalde episodes van epistaxis of nasaal ongemak ervaart bij het gebruik van Instanyl, dient een andere toedieningsvorm voor de behandeling van doorbraakpijn overwogen te worden. De totale blootstelling aan fentanyl bij personen met een verkoudheid, zonder eerdere behandeling met een nasale vasoconstrictor, is vergelijkbaar met die bij gezonde personen. Tolerantie en lichamelijke en/of psychische fhankelijkheid kan optreden na herhaald gebruik van opioïden zoals fentanyl. Iatrogene verslaving na therapeutisch gebruik van opioïden komt echter zelden voor bij de behandeling van kankergerelateerde pijn. Ontwenningsverschijnselen kunnen optreden door de toediening van stoffen met opioïd-antagonistische activiteit, bijv. naloxon, of door analgetica met een gecombineerde agonistische en antagonistische werking (bijv. pentazocine, butorfanol, buprenorfine, nalbufine). Wanneer de behandeling met Instanyl wordt gestart, dienen andere toedieningsvormen overwogen te worden voor gelijktijdige behandeling van samenlopende ziektes die via de neus kunnen worden behandeld. Bijwerkingen: Met het gebruik van Instanyl kunnen typische opioïd-gerelateerde bijwerkingen worden verwacht. Vaak zullen na voortgezet gebruik van het geneesmiddel de meeste van deze bijwerkingen verdwijnen of in intensiteit afnemen. De meest ernstige bijwerkingen zijn respiratoire depressie (mogelijk leidend tot apneu of ademstilstand), circulatoire depressie, hypotensie en shock. Alle patiënten dienen nauwlettend te worden geobserveerd op deze bijwerkingen. De volgende categorieën worden gebruikt om de bijwerkingen volgens frequentie van voorkomen te rangschikken: zeer vaak (≥1/10); vaak (>1/100 en <1/10); soms (>1/1.000 en <1/100); zelden (>1/10.000 en <1/1.000); en zeer zelden (<1/10.000), niet bekend (kan met de beschikbare gegevens niet worden bepaald). Binnen elke frequentiegroep worden bijwerkingen gerangschikt naar afnemende ernst. Psychische stoornissen: Soms: afhankelijkheid, insomnia. Zenuwstelselaandoeningen: Vaak: somnolentie, duizeligheid, hoofdpijn. Soms: sedatie, myoclonus, paresthesie, dysesthesie, dysgeusie. Evenwichtsorgaan- en ooraandoeningen: Vaak: vertigo. Soms: kinetosis. Hartaandoeningen: Soms: hypotensie. Bloedvataandoeningen: Vaak: blozen, opvliegers. Ademhalingsstelsel-, borstkast- en mediastinumaandoeningen: Vaak: keelirritatie. Soms: respiratoire depressie, epistaxis, neuszweer, rhinorrhea. Maagdarmstelselaandoeningen: Vaak: misselijkheid, braken. Soms: constipatie, stomatitis, droge mond. Huid- en onderhuidaandoeningen: Vaak: hyperhidrose. Soms: pijnlijke huid, pruritus. Algemene aandoeningen en toedieningsplaatsstoornissen: Soms: pyrexie. Overige informatie: Farmacotherapeutische groep: fenylpiperidinederivaten. ATC-code: 02AB03.Kanalisatie: UR. Registratiehouder: Nycomed Danmark ApS, Langebjerg 1, DK-4000 Roskilde, Denemarken. Volledige informatie is verkrijgbaar via de lokale vertegenwoordiger in Nederland: Nycomed comed bv, Hoofddorp. In het Register ingeschreven onder EU/1/09/531/001-009. Voor ondersteunend educatief materiaal, zie www.instanyl.nl (augustus 2009)

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case report

Anesthetic management in Bartter syndrome J.J.M.G. Theunissen, clinical clerk 1 D.G. Snijdelaar, Dr., anesthesiologist 2 G.-J. Scheffer, Prof. Dr., anesthesiologist 1

1 Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands 2 Department of Anesthesiology, Gelderse Vallei Hospital, Ede, the Netherlands contactinformation J.J.M.G. Theunissen Department of Anesthesiology, Pain and Palliative Medicine Radboud University Nijmegen Medical Centre P.O. Box 9101 6500 HB Nijmegen the Netherlands Email [email protected]. T +31 24 361 90 32

summary Bartter syndrome is a rare hereditary genetic disorder (incidence: 1:1.000.000)

causing hypokalemia, increased prostaglandin E2 levels, metabolic alkalosis and an activated rennin-angiotensin-aldosterone-system with low to normal blood pressure. The anesthetic management of patients with this syndrome can be challenging and complex. In this report we present a 49 year old woman with Bartter syndrome undergoing elective capsulotomy of the right breast. During anesthesia therapy resistant low blood pressures occurred. We describe the pathological basis causing the different clinical findings, potential problems during anesthetic care as well as options for intervention. samenvatting Het syndroom van Bartter is een zeldzame genetische aandoening (incidentie: 1:1.000.000) die gekenmerkt wordt door hypokalemie, verhoogde prostaglandine E2 waarden, metabole alkalose en een geactiveerd renine-angiotensine-aldosteronsysteem systeem, met een lage tot normale bloeddruk. Anesthesie bij patiënten met dit syndroom kan complex en uitdagend zijn. Wij presenteren een casus waarin een 49 jarige vrouw met het syndroom van Bartter een electieve capsulotomie van de rechter mamma onderging. Tijdens de anesthesie ontstond een lage bloeddruk die niet reageerde op therapie. In dit artikel bespreken we de pathologische basis die de verschillende klinische bevindingen verklaren, mogelijke problemen tijdens de anesthesiologische zorg voor de patiënt met Bartter syndroom en opties voor interventie. Keywords: anesthesia, Bartter syndrome, hypotension, management, NSAID, volume expansion.

Introduction Bartter syndrome is a rare autosomal recessive disorder (incidence 1 per million [1]) caused by a primary defect in chloride, potassium or sodium transport in the thick ascending limb (TAL) of the loop of Henle of the kidney [2]. The changes caused by this disorder are similar to the changes seen after long term loop diuretic use [3]; hypokalemia, hyperreninaemia, hyperaldosteronism and consequently metabolic alkalosis. Although it is expected that patients will have low blood pressures, because

of renal salt wasting and increased renal release of vasodilating prostaglandins, these patients tend to have low to normal blood pressures due to the compensating effects of hyperaldosteronism. It is known that patients respond poorly to the vasoconstricting effects of angiotensin II (ATII) as well as to the pressor effects of norepinephrine [4, 2]. Only a few cases [5-8] of anesthetic management of patients with Bartter syndrome have been published and those published did not address all issues regarding anesthetic care.

Case report A 49 year old woman with Bartter syndrome (bodyweight: 49 kg, length: 152 cm) was scheduled for elective capsulotomy of the right breast. Her medical history consisted of a perforation of the stomach (caused by long term indomethacin use), breast sparing surgery, breast augmentation, spondylodesis of the back and a previous capsulotomy of both breasts. Unfortunately, no old anesthetic records were available. The patient used diclofenac/misoprostol (Arthrotec®),

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Electrolytes (mmol/l)

Preoperatively

Peroperatively

Postoperatively

Normal range

Calcium

2.44

Phosphate

0.86

2.2 - 2.5 0.8 - 1.5

Magnesium

1.13

0.65 - 1.1

Sodium

134

137

138

135 - 147

Potassium

4.0

4.0

2.9

3.5 - 5.1

Chloride

100

95 - 107

Table 1. Electrolyte values pre, per and postoperatively.

omeprazol, vitamin B complex and high doses of potassium chloride (3 x 3000mg/day). Preoperatively an endocrinologist was consulted and K+, Na+, Cl-, Ca2+, Mg2+ and PO43- were determined and normal values were found (Table 1). No premedication was given. Before induction of anesthesia, cefazoline (1000 mg) to prevent infections, and dexamethason (5 mg) to prevent nausea and vomiting, were given. Anesthesia was induced with sufentanil 15 micrograms and propofol which was slowly titrated to its clinical effect; a total dose of 150 mg propofol was given. One minute after induction of anesthesia a first attempt to introduce a laryngeal mask airway was made. Since the patient was still responsive during this attempt an additional 50 mg of propofol was given. A second attempt of inserting a laryngeal mask airway was successful. A bladder catheter was inserted. Anesthesia was maintained with propofol (6 mg/kg/ hour). Just before incision sufentanil 10 microgram was given. The surgical capsulotomy was uneventful (total procedural time 46 minutes) but anesthetic management was complicated by low blood pressures (Figure 1) from the start of induction of anesthesia despite fluid therapy (1000 ml of Ringers Lactate and 500 ml of a hydroxyethyl starch solution (Voluven®)), Trendelenburg position, administration of diclofenac (75 mg) and repeated doses of phenylephrine 0,1 mg. Besides the continuous infusion of propofol no other anesthetic drugs were given during the procedure. During anesthesia patient produced around 50 ml of urine. Total blood loss was less than 50 ml. Postoperatively our patient made a full recovery but developed hypokalemia on the first postoperative day which was managed with a single infusion of 20

mmol KCl and by allowing patient to take her normal oral doses of potassium chloride. On the morning of the first postoperative day the bladder catheter was removed. Unfortunately, the total amount of urine was not noted. Discharge was on the morning of the second postoperative day.

Discussion Bartter syndrome is caused by an abnormal function of the TAL of the loop of Henle in the medulla of the kidney. Normally concentration of urine is regulated in the TAL. In this concentration process, the furosemide-sensitive Na+/K+/2Cl-symporter, located in the TAL of the loop of Henle, plays an important role. Together with the 3Na+/2K+ATPase-antiporter, chloride channels and the so-called “renal outer medullary potassium channel” (ROMK) this symporter causes sodiumchloride to be transported into the interstitium which in turn causes a rise in osmolality in the medullary interstitium. The resulting hyperosmolality in the interstitium causes an osmotic gradient and passive diffusion of water into the interstitium of the descending loop of the loop of Henle, resulting in concentration of urine. For a schematic overview of normal electrolyte transport in the TAL (Figure 2). Although different subtypes of Bartter syndrome exist (depending on the type of genetic defect) similar clinical features are found [2]. All subtypes concern a defect in one of the different transporters (Na+/K+/2Cl- symporter, chloride channel or ROMK) within the TAL. Any of these subtypes causes a failure to reabsorb chloride which results in a failure to reabsorb sodium, accumulation of salt in the distal tubule and finally in excessive salt and water loss from the body. Consequently, a state of extracellular

fluid contraction occurs. The excessive amounts of sodium offered in the distal collecting tubule are exchanged for potassium and hydrogen, which increases potassium and hydrogen secretion. All together, this explains two of the cardinal features of Bartters syndrome: hypokalemia and metabolic alkalosis. Also, loss of the voltage difference between lumen and interstitium decreases Ca2+, K+ and Mg2+ transport in the TAL and increases its excretion. This is especially relevant for calcium as hypercalciuria can cause nephrocalcinosis. Excessive loss of salt and water causes hypovolemia, stimulating the renin-angiotensin-aldosterone system (RAAS). Aldosterone increases potassium and hydrogen excretion in the collecting duct even more, contributing to the hypokalemia and alkalosis. High aldosterone and other sodium retaining hormones also increases the peptidase kallikrein [9, 10] which in turn causes a rise in vasodilatory kinins (bradykinin and kallidin) and eventually production of the vasodilator prostaglandin E2 (PGE2). PGE2 production is also stimulated by high levels of ATII [9]. The reduction in plasma volume causes the antidiuretic hormone arginine-vasopressin (AVP) to be secreted. Since AVP has its effect partly due to stimulation of the “Na+/K+/2Cl--symporter” and as PGE2 antagonizes the effect of AVP induced antidiuresis [11], AVP release is not sufficient to increase intravascular volume. For an overview of the complex interactions the reader is referred to Figure 3. The low blood pressure that was observed during surgery can have a number of causes which can be categorized in two main groups. First, anesthetic management is a major factor in inducing and/or maintaining the hypotension. Secondly, the pa-


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Figure 1. Heart rate and blood pressure during the surgical procedure.

thophysiology of Barrter’s syndrome predisposes the patient to a low blood pressure. Blood pressure is mainly determined by systemic vascular resistance and cardiac output. The use of propofol is known to cause vasodilatation as well as bradycardia, the latter possibly reducing cardiac output and thus aggravating hypotension. At the start of the procedure, baseline blood pressure was 118/78 mm Hg and heart rate was around 90 bpm. After induction both blood pressure and heart rate dropped considerably. It can be assumed that the drop in heart rate is an important cause of the low blood pressure in our patient. Also, the total induction dose of propofol (around 4 mg/kg) was quite high but was necessary because the patient was still responsive during the first attempt to insert a laryngeal mask airway. The use of an opioid in combination with propofol increases its effect on heart rate, lowering it even more. Anesthesia in patients with Bartter syndrome is known to be accompanied by low blood pressures. The literature suggests a couple of specific strategies to manage this low blood pressure; the use of NSAIDs and volume expansion. NSAIDs can correct many of the clinical and biochemical abnormalities in Bartter syndrome [10]. Furthermore, the responsiveness to ATII and α-1 adrenergic receptor agonist is increased when NSAIDs are given [12, 13]. Momeni et al. described a successful treatment of vasodilatory shock in a patient with Bartter syndrome with the NSAID ketorolac [14].

Volume expansion seems to increase the responsiveness to pressor actions [9, 12]. However, in our patient, administrating diclofenac did not raise the blood pressure or increased the responsiveness to phenylephrine. It could be that the hypotensive effect of the anesthesia itself was too strong to be counteracted by a possible effect of NSAIDs on the hypotensive “effect” of Bartter syndrome. Furthermore, our patient was using NSAIDs on a chronic base which has possibly led to low levels of prostaglandins or to a lower responsiveness to this type of medication. The non, or lower, response to vasopressor activity of α-1 adrenergic receptor agonists is a common feature in Bartter syndrome [5, 14] and has been suggested to be caused by chronic hypovolemia as well as increased kallikrein-kinin and PGE2 activity [9]. Another important feature is a poor response to pressor action of ATII which can be attributed to similar mechanisms but also to a down-regulation of ATII receptors [9, 12]. Furthermore, abnormal ATII signal transduction in Bartter syndrome was described by Calo et al [15]. It can’t be excluded that the low heart rate in our patient might be a major factor contributing to the low blood pressure. Therefore, simply raising the heart rate might have been a therapeutic option. The use of a drug like ephedrine which, in contrast to phenylephrine, also stimulates β1receptors, could have solved the problem of the hypotension. However, in the published case-reports the use of atropine and/or other β1-receptors

agonists were not effective in preventing or treating hypotension during surgery [7, 14]. Another pharmacological option would be to stimulate the vasopressin system. Although raised levels of PGE2 antagonizes the effect of normally produced AVP, administration of a synthetic vasopressin analog is an option to be considered, especially in combination with NSAIDs. Except blood pressure management, a number of other potential problems may arise in patients with Bartter syndrome undergoing surgery. First, hypokalemia predisposes to cardiac arrhythmias. However, a study on the frequency of arrhythmias in Bartter syndrome showed that arrhythmias were uncommon [16]. Animal experiments showed that a state of chronic hypokalemia causes adaptation of cardiac fibers, but it is not known if these results can be extrapolated to humans [16]. Secondly, it is well known that hypokalemia prolongs the paralyzing effect of some nondepolarizing muscle relaxants. Thirdly, as described above, patients with Bartter syndrome could have a high urinary output caused by a decreased concentrating ability of the kidney, as seen in patients using loop diuretics. Therefore, placing a bladder catheter is necessary, even in short procedures. Finally, platelet aggregation is diminished. In Bartter syndrome this is caused by increased levels of 6-ketoPGE1, a metabolite of prostacyclin which has anti-aggregation effects itself but a very short half-life [17]. Therapy with NSAIDs corrects the source of this problem, increased prostaglandin

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Figure 2: Schematic overview of normal electrolyte transport in the thick ascending limb of the loop of Henle.

production, but causes dysfunction of platelet aggregation by inhibiting thromboxane A, which normally activates new platelets as well as increases platelet aggregation in clot formation. In any way, patients with Bartters syndrome have dysfunctional coagulation that may be clinically relevant. In conclusion, Bartter syndrome is an interesting and complex disease that has an effect on many features of

Figure 3: Pathophysiology of Bartter syndrome. The primary defect in the Na+/K+/2Cl--symporter, renal-outer-medullarypotassium channel (ROMK) or chloride channel results in decreased chloride absorption. This leads to increased NaCl delivery at the distal nephron and consequently metabolic alkalosis, hypokalemia, hyperreninaemia, hyperaldosteronism, normotension and a lowered or absent response to angiotensin 2 (AT-II) and norepinephrine (NE). AVP: arginine vasopressin.

normal physiology and is challenging in anesthetic care. Especially the treatment of hypotension during anesthesia can be complex. When surgery is performed on a person with Bartter syndrome close collaboration with an endocrinologist, the potential effects of hypokalemia, dysfunctional platelet aggregation and insertion of a bladder catheter should be considered.

Acknowledgement: The helpful comments of Dr. L.B. Hilbrands, nephrologist, were highly appreciated.

references 1. Ji W., Foo J.N., O’Roak B.J. et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 2008; 40: 592-599. 2. Shaer A.J. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci 2001; 322: 316-332. 3. Jamison R.L., Ross J.C., Kempson R.L., Sufit C.R., and Parker T.E. Surreptitious diuretic ingestion and pseudo-Bartter’s syndrome. Am J Med 1982; 73: 142-147. 4. Bartter FC. Bartter’s syndrome: a disorder of vascular reactivity. Arthur C. Corcoran Memorial Lecture. Hypertension 1981; 3: I69-I73. 5. Abston P.A. and Priano L.L. Bartter’s syndrome: anesthetic implications based on pathophysiology and treatment. Anesth Analg 1981; 60: 764-766.

6. Roelofse J.A. and van der Westhuijzen A.J. Anesthetic management of a patient with Bartter’s syndrome undergoing orthognathic surgery. Anesth Prog 1997; 44: 71-75. 7. Higa K., Ishino H., Sato S., and Dan K. Anesthetic management of a patient with Bartter’s syndrome. J Clin Anesth 1993; 5: 321-324. 8. Vetrugno L., Cheli G., Bassi F., and Giordano F. Cardiac anesthesia management of a patient with Bartter’s syndrome. J Cardiothorac Vasc Anesth 2005; 19: 373-376. 9. Guay-Woodford L.M. Bartter syndrome: unraveling the pathophysiologic enigma. Am J Med 1998; 105: 151-161. 10. Vinci J.M., Gill J.R., Jr., Bowden R.E. et al. The kallikrein-kinin system in Bartter’s syndrome and its response to

prostaglandin synthetase inhibition. J Clin Invest 1978; 61: 1671-1682. 11. Tamma G., Wiesner B., Furkert J. et al. The prostaglandin E2 analogue sulprostone antagonizes vasopressin-induced antidiuresis through activation of Rho. J Cell Sci 2003; 116: 3285-3294. 12. Fujita T., Ando K., Sato Y., Yamashita K., Nomura M., and Fukui T. Independent roles of prostaglandins and the renin-angiotensin system in abnormal vascular reactivity in Bartter’s syndrome. Am J Med 1982; 73: 71-76. 13. Silverberg A.B., Mennes P.A., and Cryer P.E. Resistance to endogenous norepinephrine in Bartter’s syndrome: reversion during indomethacin administration. Am J Med 1978; 64: 231-235. 14. Momeni M., Lois F., and Jacquet L. Vasodilatory shock during cardiopulmonary bypass in Bartter syndrome.

J Cardiothorac Vasc Anesth 2008; 22: 746-747. 15. Calo L.A. Vascular tone control in humans: insights from studies in Bartter’s/Gitelman’s syndromes. Kidney Int 2006; 69: 963-966. 16. Blomstrom-Lundqvist C., Caidahl K., Olsson S.B., and Rudin A. Electrocardiographic findings and frequency of arrhythmias in Bartter’s syndrome. Br Heart J 1989; 61: 274-279. 17. Clive D.M., Stoff J.S., Cardi M., MacIntyre D.E., Brown R.S., and Salzman E.W. Evidence that circulating 6keto prostaglandin E1 causes the platelet defect of Bartter’s syndrome. Prostaglandins Leukot Essent Fatty Acids 1990; 41: 251-258.

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case report

BAV, TAA and TEE V. Gerling, MD, FANZCA 1 W. Buhre, MD, PhD 1 L. van Herwerden, MD, PhD 2

1 Department of Anesthesiology, University Medical Center Utrecht, The Netherlands 2 Department of Cardiothoracic Surgery, University Medical Center Utrecht, The Netherlands contactinformation Volker Gerling University Medical Center UtrechT Department of Anesthesiology Q building, room Q.04.2.317 PO Box 85500 3508 GA Utrecht The Netherlands T +31 (0) 88 7555 555 F +31 (0) 30 2541828 Email [email protected]

summary A 36 year old patient was admitted to our hospital with an acute dissection of his ascending

aorta. He was scheduled for emergent surgery involving replacement of his ascending aorta. The surgical plan was modified when intraoperative transesophageal echocardiography demonstrated a bicuspid aortic valve. The final operation involved a Bentall procedure with replacement of the aortic valve, aortic root and ascending aorta and re-implantation of the coronary arteries under a short period of deep hypothermic cardiac arrest. The patient made an uneventful recovery. After description of our patient’s case, we review the literature with regard to aortic dissection and bicuspid aortic valve. Our case report confirms the value of intraoperative transesophageal echocardiography with regards to diagnosing previously unknown pathology and its ability to change the anesthetic or surgical management. samenvatting Een 36 jarige patiënt werd in ons ziekenhuis opgenomen voor een chirurgische behandeling van een acute dissectie van zijn aorta ascendens. De geplande operatie werd aangepast toen perioperatieve transesophageale echocardiografie een tot dan toe onbekende bicuspide aortaklep aantoonde. De operatieve behandeling omvatte vervolgens een Bentall procedure, hetgeen inhoudt: vervanging van aortaklep, aortawortel en aorta ascendens en reïmplantatie van de coronairen, onder kortdurend diep hypotherm arrest. De patiënt herstelde spoedig en werd zonder complicaties ontslagen. Na beschrijving van de casuïstiek volgt een kort review van de relevante literatuur. Onze casus is een van de vele voorbeelden van de waarde van perioperatieve transesophageale echocardiografie voor diagnostiek van pathologie en de invloed hiervan op het anesthesiologische en chirurgische beleid.

Introduction We describe the case of a 36 year old patient who presented at our institution with an acute dissection of his ascending aorta. His medical history revealed neither cardiovascular or autoimmune disease nor any family risk factors. On the day of admission the patient suddenly developed acute, sharp and tearing chest pain while doing house maintenance work. The pain was located retrosternally, with radiation to the anterior aspect of neck and chin, coming in waves and never stopping. A consulted general practitioner heard a cardiac murmur on chest auscultation, and referred the patient to our hospital without further delay. Here, the patient was asymptomatic except for chest pain. He displayed normal vital signs, no widened pulse pressure, no difference of upper limb blood pres-

sure and normal peripheral perfusion. Laboratory investigation, chest X-ray and electrocardiogram were normal. A transthoracic echocardiography examination was not performed, for reasons retrospectively unknown. Computed tomography of chest and abdomen revealed an acute aortic dissection, extending from the aortic valve along the entire length of the aorta into the left iliac artery. Right carotid, left subclavian and left renal artery originated from the false lumen. After diagnosis of a Stanford type A dissection, emergency surgery was scheduled to replace the ascending aortic arch, without replacement of the aortic valve. Induction of anaesthesia and placement of a transesophageal echocardiography probe was uneventfully. Examination of heart and aorta revealed a mildly regurgitant aortic valve, a dilated aortic

root with a diameter of nearly 5 cm, and a dissection of the ascending aorta from 2 centimeters above the aortic valve extending through the aortic arch into the descending aorta. No cardiac tamponade and no regional wall motion abnormalities of the left ventricle were found. Closer inspection alluded to a previously unknown bicuspid aortic valve. This echocardiographic diagnosis was confirmed during the operation, and surgery concluded uneventfully with a composite graft replacement of aortic valve, aortic root and ascending aorta, with re-implantation of the coronary arteries into the graft (Bentall procedure). The operation involved only 18 minutes of deep hypothermic cardiac arrest, without selective perfusion of the carotid arteries. Intraoperative epi-aortic scanning of the distal graft anastomosis displayed no blood flow in


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Figure 1. Echocardiography color flow Doppler of distal ascending aorta anastomosis. Color flow Doppler showing no blood flow in the false lumen at the anastomosis of the ascending aorta prosthesis.

the false lumen (Figure 1 and 2) despite the fact that multiple re-entry points existed in the descending aorta (Figure 3). No re-entries in the aortic arch could be found. Postoperatively, the patient made an uneventfully recovery. He was discharged from our Intensive Care Unit on postoperative day two, and into rehabilitation on postoperative day thirteen without signs of organ malperfusion. A computed tomography before discharge and after 4 months demonstrated thrombosis of the right carotid, left subclavian and left renal artery without blood flow or signs of progression of the dissection. Further evaluation of our patient’s and his family history did not show any cardiovascular, congenital or tissue diseases. The etiology of our patient’s aortic dissection remains uncertain.

Discussion In the general population, the International Registry of Aortic Dissection (IRAD) documents aortic dissections with an incidence of 0.5 to 3 in 100000 per year [1]. Primary clinical symptoms in nearly all patients are sudden onset chest and/or back pain, with its intensity being described by 90% of patients as the worst pain ever experienced. Around 85% of aortic dissections occur without aortic aneurysm formation, and approximately 10% of patients do not present with chest pain or pulse deficit [1, 2]. More than 70% of patients have nonspecific clinical symptoms of varying severity. Standard chest X-ray document normal findings in 40% of

Figure 2. Echocardiography color flow Doppler of distal ascending aorta anastomosis. Color flow Doppler showing no blood flow in the false lumen at the anastomosis of the ascending aorta prosthesis.

cases, and ECG is abnormal in around 70% of cases showing non specific ST changes, left ventricular hypertrophy, or signs of myocardial ischemia and infarction [1]. The non specific clinical symptoms can delay or falsify a diagnosis in up to 40% of patients [1-3]. Sensitivity and specificity of helical computed contrast tomography, magnetic resonance imaging and transesophageal echocardiography for detection of an aortic dissection are 95-100% [2-4]. Transthoracic echocardiography is reported to have a sensitivity of 59-83% and specificity of 63-93% for diagnosis of aortic dissection, with a sensitivity of 78-100% for a type A dissection [4]. Main cardiovascular risk factor for aortic dissection in >85% of older patients is arterial hypertension, followed by atherosclerosis and previous aortic surgery. In the younger population, pathophysiology relates more to connective tissue diseases (e.g. Marfan’s disease) or congenital malformations (for example bicuspid aortic valve). Once an entry point in the intimal aortic layer has developed, blood can travel relatively freely ante- and retrograde through the medial layers of the aorta. Mortality rate of untreated dissection has been estimated to be around 1-2% per hour during the first 48 hours, 89% at 14 days, and 90% at 3 months [1-3, 5, 7, 8, 10]. Cardiovascular complications depend on the pressure gradient between the true and false lumen. The main acute complications are aortic rupture, cardiac tamponade, heart failure or other end-organ ischemia. Longterm com-

plications include progression of the dissection, aneurysm formation, aortic rupture at the weakened false lumen, and refractory arterial hypertension [2, 3]. The prognosis of an acute aortic dissection is poor in the elderly population, in the presence of several comorbidities or for those patients presenting in hemodynamic shock. Some 50% of patients die within 30 days. The acute in-hospital mortality of patients undergoing surgery is above 25%, depending on preoperative status, surgical complications and postoperative end-organ ischemia [1]. Data are scarce, but survival after 10 years with a median 5 year follow-up seems to range from 35% to 70%. Probably more than 50% of surviving patients return to an independent life [2]. Some 400 years ago, Leonardo da Vinci was most likely the first to describe a bicuspid aortic valve (Figure 4) [8]. In the general population a bicuspid aortic valve occurs in up to 4% [1, 3]. Nearly all patients with this pathology will require surgery during life, and up to 50% of these patients will present with an (acute) aortic dissection, 9% being younger than 40 years. Dilatation of the ascending aorta and aortic arch is generally found in patients above 40 years of age, with diameters increasing by 0.2-0.9 millimeters per year due to relevant hemodynamic shear stress [2, 4, 6, 7]. The median age at the time of operation is 50 years of age. Strong genetic influence and an autosomal dominant pathway in around 30% of cases make it mandatory to further investigate patients and their first degree family members for (cardio-

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Figure 3. Transesophageal echocardiography color flow Doppler in descending aorta demonstrating entry points from true into false lumen. Color flow Doppler showing blood flow from the true lumen into the false lumen through multiple entry points in the dissection flap in the descending aorta.

vascular) congenital malformations [3, 6, 8, 9]. Patient treatment is not based on randomized controlled trials but on case series, registries, case reports, consensus documents, systematic reviews and local expertise. It aims at restoring blood flow and pressure within the true lumen, with subsequent compression of the false lumen, thus normalizing aortic blood flow. The highest immediate treatment priority is pharmacological control of systolic blood pressure to discourage further disease progression, together with close monitoring for signs of aortic rupture or organ failure. What seems to be crucial in the prevention of long-term complications are lifestyle changes to modify cardiovascular risk factors, restrict physical activity, and exert strict blood pressure control with betablockers to maintain systolic blood pressures at less than 130 mmHg [2, 3, 6]. To allow risk stratification, several classifications have been developed, including the Stanford, De Bakey, and Svensson classification. An operation is necessary in patients suffering from

Figure 4. Bicuspid Aortic Valve by Leonardo Da Vinci. Drawing of Leonardo Da Vinci depicting most likely a bicuspid aortic valve in the right upper corner of the drawing. Braverman AC et al: The bicuspid aortic valve. Curr Probl Cardiol 2005; 30(9):470-522.

Stanford type A dissection and can involve replacement of the ascending aorta with or without aortic valve replacement, of the aortic (hemi-)arch and coronary bypass grafting. The anatomy of the aortic arch is relevant for the immediate and late prognosis of the patient, defining the risk of late false aneurysm dilatation and rupture. At our institution, we favor an aggressive policy for aortic arch replacement if extensive re-entries around aortic arch branches exist. Although it is debated internationally, in our patient we performed an aortic valve replacement as opposed to our general strategy of aortic valve repair. Our decision was based on his high risk of future surgery of the bicuspid aortic valve, his mild aortic valve regurgitation and the size of the patient’s proximal aortic root.

Conclusion We found that our patient taught us some important lessons. Firstly, luck by chance is an important feature in survival. Due to the nonspecific nature of his symptoms, our patient only survived

because he visited a general practitioner with attention to detail. Without a thorough physical examination and auscultation of his chest, our patient would most likely have not lived into the near future. Innocent chest pain does indeed in rare cases conceal significant pathology, even in the apparently young and healthy patient. This underlines the necessity to approach every patient unprejudiced, evaluating and re-assessing all clinical and diagnostic findings without pre-formed assumptions. Secondly, our case demonstrates that standard everyday diagnostics like chest X-ray or electrocardiogram have a relatively low sensitivity and specificity. If no conclusive diagnosis can be reached, the use of more advanced diagnostic tools is mandatory. At last, our case is one of many reminders in the literature demonstrating the ability of (intraoperative) echocardiography to diagnose unknown pathology or to modify an anesthetic or surgical plan, emphasizing its value in everyday clinical practice.

references 1. Hagan P.G et al: The International Registry of Acute Aortic Dissection (IRAD). JAMA 2000; 283(7):897-903. 2. Golledge J., Eagle K.A.: Acute aortic dissection. Lancet 2008; 372:55-66. 3. Elefteriades J.A.: Thoracic aortic aneurysm: reading the enemy’s playbook. Curr Probl Card 2008; 33:203-77. 4. Meredith E.L., Masani N.D.: Echocardiography in the emergency as-

sessment of acute aortic syndromes. Europ J Echocardiography 2009; 10:131-139. 5. Borger M.A. et al: Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004; 128:677-83. 6. Erbel R. et al: Diagnosis and management of aortic dissection. Recommendations of the Task Force on

Aortic Dissection, European society of Cardiology. Europ Heart J 2001; 22:1642-1681. 7. Cecconi et al: Aortic dilatation in patients with bicuspid aortic valve. J Cardiovasc Med 2006; 7(1):11-20. 8. Braverman A.C. et al: The bicuspid aortic valve. Curr Probl Cardiol 2005; 30(9):470-522. 9. Etz C.D. et al: Longterm survival after the Bentall procedure in 206

patients with bicuspid aortic valve. Ann Thorac Surg 2007; 84(4):118694. 10. Flachskamp F.A.: Assessment of aortic dissection and hematoma. Semin Cardiothorac Vasc Anesth 2006; 10(1):83-8.

Perifere Neuropathische Pijn

Het ondraaglijke kalmeren

LYR-10-084 augustus 2010

Lyrica. Snelle en aanhoudende (1-5) pijnverlichting

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review

Acute Porphyria Pandora’s box in perioperative care K. Ariese, Drs MD 1 T.A. Brans, Drs MD 2 M.J. van den Elsen, Dr. MD PhD 2 S.A. Loer, Prof. Dr. MD PhD 1 C. Boer, Dr. PhD 1

1 Department of Anesthesiology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands 2 Department of Anesthesiology, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, 1061 AE Amsterdam, the Netherlands contactinformation Karin Ariese Department of Anesthesiology VU University Medical Center De Boelelaan 1117 1081 HV Amsterdam T +31 (0) 20 4444386 F +31 (0) 20 4444385 Email [email protected]

samenvatting Porfyrieën worden veroorzaakt door enzymafwijkingen die betrokken zijn bij de biosynthese van, onder andere hemoglobine, myoglobine en cytochromen. Porfyrieën zijn relatief zeldzaam, maar kunnen niettemin acuut optreden in de perioperatieve periode en leiden tot ernstige mortaliteit en morbiditeit. Herkennen van een porfyrinogene constitutie is daarom essentieel ten einde optimale perioperatieve zorg te bieden gedurende een acute porfyrinogene episode en om het ontstaan van een porfyrinogene crisis te vermijden. In 2000 publiceerden James & Hift een uitgebreide review van de bestaande literatuur, met name gericht op anesthesiologische overwegingen betreffende patiënten met porfyrie. In de periode van 2000 tot nu zijn nieuwe inzichten, case reports en internet-informatie gepubliceerd, welke van toegevoegde waarde zouden kunnen zijn voor de anesthesioloog om een porfyrinogene episode te voorkomen of te behandelen. Daarom onderzochten wij recente literatuuren internetbronnen op het ontstaan van een porfyrinogene episode in de perioperatieve periode. Tevens worden hier de betreffende eigenschappen van diverse anesthesiologische medicamenten beschreven, gevolgd door een samenvatting van alle relevante case reports die mogelijk van belang zijn voor de anesthesiologische praktijk. Uit onze review blijkt dat moderne anesthesiologische toepassingen een veilig perioperatief beleid mogelijk maken, en daardoor het risico verminderen op het ontwikkelen van een acute porfyrinogene crisis. Porfyrieën manifesteren zich als ‘Pandora’s box’ in de perioperatieve setting, en zorgvuldige preoperatieve assessment en toegewijde perioperatieve zorg kunnen samen leiden tot vermindering van het risico op intra- en postoperatieve complicaties.

Introduction Although rare, latent porphyrias may have detrimental effects on patient outcome, in particular during perioperative care. However, due to the rarity of this disease, the literature lacks systematic research concerning the risks of anesthesia in porphyrinic patients. Porphyria originates from the Greek word porphura, which means ‘purple pigment’ and refers to the purple discoloration of skin and urine during an episode of porphyria. The disease was first biochemically explained in 1847 by Felix Hoppe-Seyler, and in 1889 the Dutch physician B.J. Stokvis described the first

acute cases of porphyria [1, 2]. The term porphyria refers to a heterogeneous group of metabolic diseases caused by enzymatic defects in the biosynthesis of haem, the central component of the oxygen transporter hemoglobin. In addition to hemoglobin, haem is an essential component in the synthesis of myoglobin, catalase, peroxidase and respiratory and P450 liver cytochromes [3, 4]. In porphyrias, haem precursors are excessively produced and they subsequently heap up in various tissues and organs. The accumulation of haem in the body may lead to neurovisceral and/or photocutaneous symptoms

and purple colorization of tissues and organs. The physiological disturbances as induced by haem accumulation are associated with increased morbidity and mortality [5-10]. Porphyrias are classified as hepatic or erythropoietic porphyrias, based on the characteristic origin overproduction and accumulation. Patients with porphyria commonly present in three different ways with cutaneous lesions, acute attacks, or both [9]. The prevalence of porphyria varies widely from country to country and depends on the type, of which porphyria cutanea tarda (PCT) and acute intermittent porphyria (AIP) are the most widespread


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Figure 1. Metabolic pathway of haem synthesis. Distinct enzymatic reactions are indicated by numbers which correspond with table 1.

[7, 9, 11, 12]. Despite this low prevalence, it is important that anesthesiologists have insight in the pathophysiological process, clinical signs and treatment of these diseases since acute porphyrias may typically be induced by anesthetic strategies. Furthermore, anesthesiologists may be involved in the treatment of this disease during an acute episode, which consists of cardiovascular support, mechanical ventilation and analgesia. Indeed, anesthetic agents like etomidate, barbiturates, clonidine and benzodiazepines are among the drugs that may precipitate acute attacks of porphyria [13, 14]. We briefly address new insights in pathophysiology, classification and symptoms of the porphyrias. Secondly, the diagnosis and management of acute porphyrias will be described in the light of perioperative care. We focus on recent case reports that describe the effects of perioperatively used agents in porphyrinic patients and based this article on literature reviews and case reports using Medline search, particularly focusing on publications in the period of 20002008. Drug recommendation is based on four highly qualified [15] internet porphyria databases which classify drugs that may precipitate porphyria: 1) Porphyria South Africa (PSA; http://www.uct.ac.za/); 2) the European Porphyria Initiative (EPI; http://www.porphyria-europe.com/); 3) the Australian National Research Centre for Environmental Toxicology (EnTox; www.uq.edu.au/porphyria/) and 4) the

Enzyme

Syndrome

Abbr. Origin

1

ALA synthase

Mitochondrium X-linked anemia

XLSA Erythropoietic

2

ALA dehydratase

ALAD porphyria

AP

Hepatic

3

HMB synthase

Acute intermittent porphyria

AIP

Hepatic

4

Uroporphyrinogen

Congenital erythropoietic porphyria CEP

Erythropoietic

5

UROS

Porphyria cutanea tarda

PCT

Hepatic

6

UROD

Hereditary coproporphyria

HCP

Hepatic

7

Protoporphyrinogen Variegate porphyria

VP

Mixed

8

Ferrochelatase

EPP

Erythropoietic

Erythropoietic protoporphyria

Table 1. Overview of the enzymes involved in distinct types of porphyria. Syndromes are abbreviated (Abbr.) and the origin of the enzymatic disorder is presented for all distinct diseases.

American Porphyria Foundation (APF; http://www.porphyriafoundation.com/) [16-19].

Physiology and pathophysiology Haem synthesis The porphyrins play a critical role in biology, since they are involved in a wide range of reactions related to oxygen utilization, transport, storage or formation. In human physiology, haem is the most important of the porphyrins [4]. Although haem is synthesized in every human cell, about 85% is made in erythrocytes, predominantly for hemoglobin formation. Most of the remainder is produced in the liver, where 80% is used for the creation of different cytochromes [7]. A partial deficiency of one of the enzymes in the haem synthesis pathway causes characteristic clinical and biochemical features. These disorders are due to a specific alteration in the pattern of accumulation of porphyrin and porphyrin precursors. Figure 1 illustrates the synthesis cascade of hemoglobin, and depicts the enzymes that are involved in the pathophysiology of porphyrias. Signs and symptoms The multifactorial character of porphyriarelated morbidities is based on the combination of genetic disorders with exogenous precipitation factors like drug exposure, hormonal fluctuations and infections [20-24]. Porphyrias are panethnic and their prevalence varies

from 0.5 to 10 per 100.000 in different populations [8, 25-27]. The porphyrias are defined according to the deficient enzyme, the location of abnormal porphyrin production (hepatic or erythropoietic) and according to the potential risk of an acute attack (table 1). The latter method of classification is particularly useful for anesthetic practice, as only the acute forms may be precipitated by perioperative interventions resulting in lifethreatening reactions [3, 13,28, 29]. Acute porphyrias are characterized by acute episodic neurological, psychiatric and gastrointestinal symptoms, usually followed by complete remission, although fatalities due to respiratory or renal failure may occur [5, 30-32]. Episodes are rare before puberty, when a rise in the sex steroids enhances delta-ALA synthase activity. Acute attacks may be precipitated by alcohol, smoking, party drugs, sex steroids, stress, fasting, dehydration, surgical lesions and several drugs [3, 33,34]. The most common neurovisceral complaints are abdominal pain, vomiting, constipation, muscle weakness, mental symptoms, limb-, head-, neck- or chest pain, hypertension, tachycardia, convulsion, sensory loss, fever, respiratory paralysis and diarrhea. Acute attacks may be combined with metabolic disorders such as dehydration, hyponatremia, hypokalemia, hypomagnesemia and inappropriate secretion of ADH [8, 20, 35-37]. The nonacute porphyrias are divided into cutaneous porphyrias and the erythropoietic

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porphyrias. In cutaneous porphyria, photo-oxidation of porhyrinogens cause accumulation of porphyrins in the skin leading to photosensitivity [38, 39]. The accumulated porphyrins cause skin damage through exposure to ultraviolet light, with subsequent production of tissuedamaging reactive oxygen species. Cutaneous photosensitivity often begins in childhood, affects sunexposed areas, and is generally worse in spring and summer. Common symptoms include itching, painful erythema and swelling, which can develop within minutes of sun exposure. Additionally, petechiae, purpuric lesions, chronic blistering lesions, photosensitive ocular diseases and secondary infection may also occur. The erythropoietic porphyrias are associated with varying degrees of hemolytic anemia, presumably due to photolysis as porphyrin-loaded erythrocytes are exposed to light in the dermal capillaries [11,12,40]. This may result in hemolysis and splenomegaly and, in the case of lifelong anemia, compensatory expansion of erythroid marrow and pathologic fractures [11, 12, 40]. Diagnosis There are several laboratory tests available to detect porphyria in blood, urine or stool, which can be alienated into tests for clinically expressed porphyrias and the detection of genetic predisposition [20, 35, 41]. Especially the demonstration of porphyrin precursors like ALA and/or PBG plays a central role in the diagnosis of acute hepatic porphyrias [11]. However, samples of urine or blood should be taken during the acute attack of porphyria and it may however be necessary to repeat PBG and/or ALA testing over time, since levels may fluctuate towards normal levels [41]. Furthermore, analysis of porphyrins is necessary to demonstrate porphyrias with cutaneous photosensitivity [12]. Since most acute porphyrias are dominantly, inherited diseases, DNA or enzyme testing may be additionally applied as diagnostic tool [35, 42].

Management of an acute episode of porphyria Diagnosis of patients at risk Anesthesiologists may encounter patients with a history of porphyria who are able to describe their disease in a preoperative phase. However, de novo porphyrinic episodes may be first unrecognized and subsequently sud-

denly induced by perioperative actions and interventions. In the preoperative phase, anesthesiologists should carefully prepare patients with a known porphyrinic history and avoid all stressors that may precipitate an acute episode. Acute neurovisceral attacks are accompanied by increased urinary excretion of PBG and, to a lesser extent ALA. Monitoring of urine porphyrin levels is therefore the only way to predict an attack, and one should continue this monitoring for several days. However, since urinary PBG and ALA levels may also rise due to other diseases and habits like alcohol abuse, increased PBG and/or ALA levels may be misleading. Normal adult urine contains <1.5 µmol PBG/mmol creatinine (<10 µmol/l) and this increases at least tenfold in patients with an acute episode of porphyria. In response to this increase, one may start curative therapy as soon as possible, as described below [28]. As indicated by Anderson et al. (2005), porphyria should always be considered when initial clinical evaluation does not support other causes for abdominal illness and severe pain [20]. In that case, diagnosis of porphyria can rapidly be established by simple and fast laboratory testing for porphobilinogen levels. De novo patients may develop their first acute episode in the perioperative period due to factors like preoperative fasting, fever, illness, stress and drugs. Hormonal fluctuations may additionally contribute to cyclical attacks in women, whereas oral contraceptives, androgens, fertility and luteinizing hormones have also triggered photosensitivity. An episode may be accompanied by increased muscle strength and dysfunction of the cranial nerves, thereby inducing respiratory failure and aspiration. Furthermore, hemodynamic and cardiovascular function should carefully be monitored in order to prevent hypertension and tachycardia and the fluid and electrolyte balance should be determined. Finally, acute intermittent porphyria is an inherited metabolic disease with an autosomal dominant pattern of inheritance. Since an acute porphyrinic episode remains underdiagnosed in the absence of clinical symptoms, DNA testing might be added as helpful tool in order to perform accurate risk stratification. Perioperative prevention and treatment of acute porphyrias There are several interventions that may counter an acute episode of porphyria.

These interventions are described below. Metabolic, renal and cardiovascular control Preoperative fasting may trigger an acute crisis of porphyria. In order to prevent fasting-induced episodes, one might start a saline-glucose infusion prior to surgery in order to prevent hypoglycemia. However, pure glucose solution should be avoided because of the risk for hyponatremia during an acute crisis [3]. Due to an increased metabolic demand during acute episodes of porphyria, a highcarbohydrate diet is recommended, while severe attacks require glucose infusion [20, 42]. In contrast, treatment of hyperglycemic episodes may be safely countered by insulin [16-19]. Additionally, an acute porphyrinic crisis can be associated with impaired renal function and alterations in fluid electrolytes [43]. Renal failure and a disturbed electrolyte balance should be firmly treated in porphyrinic patients, since it may deteriorate the progression of the disease, induce seizures and influence patient outcome [44]. In particular, underproduction of antidiuretic hormone and vomiting enhance the development of fluid deprivation and hyponatremia, and should be countered by fluid resuscitation [20,30]. Furthermore, hypertension and tachycardia associated with porphyria may be safely treated by beta blocking substances like propranolol [16-19]. Treatment of acute episodes of porphyria by hemin or plasmapheresis In 1971, Bonkowsky and coworkers were the first to report the beneficial effects of the administration of hematin in a patient with a severe attack of API [45]. Since 1983, hemin has been approved as treatment of acute porphyria in the USA and subsequently several investigations were performed regarding the safety and efficacy of its hepatic ALA synthase activity repressing properties [20]. The safety and efficacy of hemin in the treatment of porphyrinic patients has repeatedly demonstrated, and this has led to worldwide registration of hemin as anti-porphyrinic drug [16-19, 46]. Hemin is administered intravenously in a prophylaxic or treatment modality (3 to 4 mg/kg once daily for 4 days), leading to decreases in urine porphobilinogen excretion and trends in clinical benefit [20, 47]. When hemin is administered early in an attack, clinical improvement is rapid and often seen within the first


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Precautions

Treatment options

Saline-glucose infusion

EPI, EnTox, PSA, APF

Hemin

EPI,EnTox, PSA, APF

Analgesia


Plasmapheresis

Not classified

Beta-blockade

EPI, EnTox, PSA

Anti-seizure medication


Anxiolytics


Anti-emetics

EPI, EnTox, PSA

Perioperative options Propofol

EPI, PSA, APF

Vecuronium/Rocuronium

EnTox, PSA

Sevoflurane, Desflurane

EnTox, PSA

Atracurium

EnTox, PSA

Nitrous Oxide

EPI, PSA

Frusemide

EPI, EnTox, PSA

Bupivacaine


Thiazides

EPI, EnTox, PSA

Morphine


Atropine

EPI,EnTox, PSA, APF

Fentanyl


Dobutamine

EPI, EnTox, PSA

Paracetamol


Dopamine

EPI, EnTox, PSA

Acetylsalicyclic acid


Phenylephrine

EnTox,

Pethidine

EPI, EnTox, PSA

Propranolol

Entox, PSA

Ondansetron

EPI, EnTox, PSA

Penicilline

EPI,EnTox, PSA, APF

Promethazine

EPI, EnTox, PSA

Azythromycin

EPI, EnTox, PSA

Dexamethasone

EPI, PSA, APF

Aminoglycosides

EPI, PSA

Midazolam

EPI, EnTox, PSA

Insulin

EPI,EnTox, PSA, APF

Table 2. Overview of treatment and anaesthesia recommendations in patients with a porphyrinic condition. Drugs that may be applied during perioperative care are all recommended by the drug databases available (EPI: European Porphyria Initiative, EnTox: Australian National Research Centre for Environmental Toxicology, PSA: Porphyria South Africa and APF:American Porphyria Foundation) [16-19].

two days [20]. A second treatment option for acute episodes of porphyria is plasmapheresis, where patient plasma is replaced by saline. Although the benefits of plasmapheresis as treatment option in an acute porphyrinic crisis are not systemically reviewed, several case reports show a reduction in heam precursors and improvement of clinical signs after plasmapheresis [48-51]. Until now, plasmapheresis has not yet been classified as treatment option in acute porphyria by the porphyria initiatives [16-19]. Other, experimental therapeutic options are the infusion of recombinant porphobilinogen deaminase [52] or (vector optimized) gene therapy [53, 54]. Pain An acute episode of porphyria is commonly associated with severe pain in the abdomen, extremities, head, back, neck or chest [20, 30]. Treatment should focus on pain relief and prevention of vomiting, since the latter may cause dehydration of the patient, thereby worsening porphyrinic symptoms [30]. In cases of severe pain, opiates like morphine and fentanyl are the first choice due to their safe profile for porphyrinic patients [55, 56]. Nausea and vomiting

can be prevented or treated by antiemetics like ondansetron and prochlorperazine. Peripheral neuropathy and seizures Porphyria may induce peripheral neuropathy and may progress rapidly into dysfunction of vital organs like the respiratory system. Frequent porphyrinic episodes that are associated with abdominal and peripheral pain may induce the development of chronic neuropathic and abdominal pain disorders. In these cases this might lead to chronic opiate usage and opiate dependency [20, 57]. Furthermore, acute episodes of porphyria may be associated with seizures which can be prevented by maintenance of an optimal balance in body fluids and electrolytes and treated by anti-seizure controls [20,57]. Pregnancy Pregnancy is associated with increased levels of hormones such as progesterone, which potentially may aggravate porphyria. Pregnant patients with a porphyrinic predisposition have a therefore a higher incidence of acute porphyrinic attacks leading to an increased maternal mortality rate, high rates of spontaneous abortion, hypertension

and low birthweight infants [58, 59]. For symptomatic patients or patients in a crisis, a combination of propofol with volatile anesthetics and opiates may be the anesthesia of choice [60]. Pharmacological precipitation of porphyrias Drug metabolism may be altered in porphyrinic subjects, and may lead to non-metabolized drug accumulation or secretion as haem is an essential component in the production of myoglobin, catalase, peroxidase and respiratory and P450 liver cytochromes [4]. Certain drugs may elevate haem synthesis, thereby leading to an increased porphyrin production and possibly porphyria [61-64]. In general, drugtherapy in porphyrinic subjects should only carefully be considered, and only when this is strictly indicated. Combinations of medicines should be avoided, and drugs ought to be chosen from the available porphyria drug databases as described below. Inadequate diagnosis or treatment of patients with porphyria may lead to irreversible complications and eventually mortality. This was faced by the Chilean novelist Isabel Allende, who described the disease history of her daughter Paula Frias Allende in the

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book ´Paula´. Paula suffered from influenza, and was administered to a hospital where physicians misdiagnosed her porphyrinic condition and oversedated her. Paula subsequently fell into a coma that led to hear death after one year [65]. Different drug classes that can be safely used in anesthesia clinical practice are described in table 2. Intravenous anesthetics Cytochromemediated drug metabolism and the high fat solubility of many anesthetics may suggest that especially these medicines possess porphyrinogenic characteristics. Most of the anesthesiarelated episodes of porphyria are indeed acute attacks, including acute intermittent porphyria (AIP), porphyria variegate (VP), hereditary coproporphyria (HCP) and ALA dehydratase deficient porphyria (AP) [63, 66-70]. There is only limited data available with regard to the porphyrinogenic characteristics of intravenous anesthetics, and most literature has an experimental or casuistic character. Barbiturates Distinct drug databases indicate that the use of barbiturates should be avoided in patients with a porphyrinogenic constitution. Indeed, longterm use of barbiturates induces the activity of the cytochrome P-450 system, thereby increasing the level of haem synthesis. Barbiturates additionally enhance the induction of ALA and aldehyde dehydrogenase, leading to ALA accumulation which may result in exacerbations of acute porphyria episodes [28, 55]. For this reason, barbiturates are used in animal studies to induce a porphyrialike syndrome on purpose [71, 72]. Due to this high risk of barbiturate-induced acute porphyria, the use of these drugs is contraindicated in known porphyrinic patients[ 28, 55]. Propofol Propofol is nowadays the most widespread used intravenous anesthetic, and has been referred to for its lack of porphyrinogenic characteristics [28, 73, 74]. Unfortunately, there is only one prospective clinical trial in 13 patients with variegate porphyria available which showed that propofol can be safely used to induce anaesthesia [75]. The remaining are case reports, in which propofol has been safely applied as bolus followed by chronic infusion up to 180 mg/kg/min in a mixed patient population. Only in the case of application of several doses

of propofol it has been shown that the level of urine porphyrins increases after an anesthesia procedure [76, 77]. Reports originating from the last ten years suggest that propofol can effectively be used as anticonvulsant during an acute porphyrinic crisis [78], or for the induction of anesthesia in patients with a porphyrinic constitution [79-82]. Propofol was combined with succinylcholine [60] or vecuronium [82], respectively. One may therefore postulate that the application of propofol in porphyrinic patients is relatively safe. Etomidate and ketamine The intravenous drugs etomidate and ketamine increased the hepatic ALAs activity and coproporphyrin and protoporphyrin content in rats [83]. The porphyrinogenic characteristics of ketamine seem especially depended on the administered dose, and clinical data suggest that application of low concentrations of ketamine is relatively safe [83-87]. The ambiguous reports with regard to the safety of etomidate and ketamine imply that application of more modern anesthetics with a short half-life, like propofol, may be preferred in patients with a porphyrinic constitution. Dexmedetomidine There are no animal or clinical data with regard to the precipitating properties of the novel anesthetic dexmedetomidine in porphyrinic patients available. Inhalational anesthetics In an experimental study, isoflurane, enflurane and sevoflurane all induced an increase in ALA synthase, whereas isoflurane and sevoflurane reduced the PBGase activity in cultured B-type lymphocytes [88]. Momentarily, there are a handful of case reports available that describe the application of modern volatile anesthetics in individual patients. Especially sevoflurane and desflurane, which can be washed out rapidly with minimal metabolization effects may be relatively safe for application in porphyrinic patients [3]. Hiraki et al. reported the use of isoflurane in a 55 year-old female with historical episodes of AIP scheduled for total hip replacement [80]. There were no porphyrinic symptoms apparent although urinary PBG was slightly increased in the preoperative phase. The patient recovered from surgery without signs of porphyria or increases in porphyrinic markers. For sevoflurane and

desflurane, similar findings were found in five different case reports describing adult and pediatric surgery [89-93]. In addition, Messmer et al. suggested that volatile anesthetics may even be used as protective intervention, as similar as hypnotics, in the prevention of precipitation of a porphyrinic attack [92]. All case reports suggest that volatile anesthetics may safely be used in the maintenance of general anesthesia. Locoregional anesthetics The occurrence of central and peripheral neuropathologic lesions in porphyrinic patients has resulted into the advice that spinal anesthesia, epidural anesthesia, or nerve blockade should be avoided in these patients [94]. On the other hand, James & Hift (2000) described that there is no evidence that locoregional anesthetics have ever induced an acute attack or neurological pathology in porphyrinic subjects, and this is confirmed by the available drug databases [3, 16-19]. Bohrer and others recommended that anesthetics like bupivacaine, prilocaine, tetracaine or procaine may safely be applied in porphyrinic patients, although data supporting these suggestions are mainly based on individuals [95-96]. With regard tot the specific population of women undergoing a caesarean section or need peripartum analgesia, a spinal approach with bupivacaine is favored [60]. Lidocaine, chirocaine, ropivacaine, bupivacaine, prilocaine, tetracaine and procaine are all classified as safe when applied as locoregional anesthetics by the majority of drug databases [16-19].

Analgesics and anti-emetics Analgesics Opioid analgesics are generally proofed to be safe in patients with a porphyrinic constitution. With regard to remifentanil, only Durmus and co-workers (2002) presented one case report where remifentanil, in combination with propofol and isoflurane, was safely applied in a Caesarean section [58]. Additionally, sufentanil has been described as a safe drug during cardiac surgery in two porphyrinogenic patients [97, 98]. Caution should be exercised in the choice of the non-opioid analgesics. Acetylsalicyclic acid and paracetamol are considered to be safe, but the use of pyrazalone (phenylbutazone) and non-steroidal anti-inflammatory drugs (NSAIDs) like naproxen, ibuprofen and diclofenac should be discouraged [67,


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Source

Porphyria

Gender

Other used drugs

Manifestation

Sarantopoulos [82] 2000

HCP

female

Midazolam, fentanyl, bupivacaine, vecuronium, neostigmine

Uneventful anaesthesia

Pandey [78]

2003

AIP

female

Propranolol, gabapentin

Stop of epileptic convulsions

Consolo [60]

2005

PV

2 females

Succinylcholine, sufentanil, bupivacaine,

Isoflurane

Hiraki [80]

2001

AIP

female

Propofol, suxamethonium, mepivacaine

Sevoflurane

Evans [89]

2001

AIP

2 females

Propofol, fentanyl, morphine, amitriptyline, Uneventful anaesthesia atracurium, prochorperazine

Takahashi [91]

2005

AIP

female

Epidural


Hsieh [90]

2006

AIP

-

Rocuronium


Sheppard [93]

2005

AIP

male

Propofol, fentanyl, vecuronium, bupivacaine, neostigmine


Messmer [92]

2004

AIP

-

Sufentanil, atracurium, bupivacaine, fentanyl

Uneventful anaesthesia, no postoperative complications

Benzodiazepine Rassiat [119]

2001

AIP

male

Benzodiazepine, alcohol

Porphyria

Barbiturate

Mseddi [120]

2002

AIP

male

Thiopental, succinylcholine

Postoperative death

Morphinomimetic

Durmus [58]

2002

AIP

female

Propofol, isoflurane, vecuronium


NSAIDs

Maerker [121]

2001

Pseudo

male

Naproxen

Pseudoporphyria

Antony [122]

2000

Pseudo

male

Nabumetone

Pseudoporphyria

Schad [123]

2002

Pseudo

2 females

Naproxen

Pseudoporphyria

O’Donoghue [124] 2002

Pseudo

male

Naproxen

Pseudoporphyria

Markus [125]

2004

Pseudo

female

Rofecoxib

Pseudoporphyria

Phung [126]

2004

Pseudo

female

Ampicillin-sulbactam, cefepime

Pseudoporphyria

DeGiovanni [127]

2007

Pseudo

male

Ciprofloxacin

Pseudoporphyria

Kwong [128]

2007

Pseudo

-

Voriconazole

Pseudoporphyria

Propofol

Desflurane

Antibiotics

Year


Table 3. Analysis of anaesthesia-related case reports as documented in Medline in 2000-2007 using the search term ‘porphyria’. The presented case reports support the safe application of propofol, isoflurane, sevoflurane, desflurane and morphinomimetics in patients with a porphyrinic constitution.

99]. Morphine, fentanyl, aspirin, naproxen, ibuprofen, pethidine and paracetamol are all classified as safe by the drug databases, whereas tramadol, nalbuphine and diclofenac should only be used with caution [16-19]. Interestingly, there are several case reports showing that naproxen use is associated with induction of an acute porphyrinic episode (see table 3), but all drug databases indicate naproxen as safe analgesic. Anti-emetics If anti-emetic therapy is indicated, metoclopramide [100] should not be used whereas ondansetron, promethazine, droperidol and chlorpromazine are accepted despite the lack of scientific argumentation [28]. Prophylaxis of postoperative nausea and vomiting (PONV) can be countered by dexamethasone [17-19].

Benzodiazepines Since preoperative psychological stress may induce an episode of acute porphyria, anxiolytica are recommended to prevent the development of an acute crisis [14, 69]. The use of benzodiazepines as anxiolytics can be considered as relatively safe in patient with a porphyrinic constitution, however the porphyrinogenic potential varies among the type of benzodiazepine [3, 28]. Lambrecht and coworkers (1999) investigated whether lorazepam, oxazepam, diazepam, triazolam and midazolam trigger porphyrin accumulation in primary cultures of chick embryo liver cells [101]. They showed that low doses of diazepam, triazolam and midazolam induced accumulation of porphyrin, whereas this accumulation was absent for low doses of lorazepam and oxazepam [101]. There is inconsistency with regard to the por-

phyrinogenic potential of diazepam in AIP [21, 72, 73, 102] whereas midazolam has been safely applied in patients with known VP [103]. Muscle relaxants James & Hift (2000) reported that neuromuscular drugs like succinylcholine can be safely used in patients with porphyria [3, 55]. Single dose administration of atracurium [59, 92, 97, 104] or vecuronium [105] has safely been used in a small number of porphyrinic patients whereas chronic use or repeated dose administration of these drugs is not recommended [28, 29]. Most muscle relaxants are classified as safe by the drug databases, but should be used with caution [18, 19]. With regard to drugs that antagonize neurorelaxantia like the cholinesterase inhibitor neostigmine or sugammadex there are no data available.

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Cardiovascular drugs Hypertension and tachycardia are well known features of acute porphyria and are related to stimulation of the sympathic nervous system and increased circulating catecholamines [106-108]. Several animal studies have suggested that sympathicolytica like propranolol may prevent deterioration of an acute attack of porphyria, but this has not yet been confirmed in patients [109, 110]. There is no uniform advise regarding the use of either catecholamines or sympathicolytica in porphyrinic patients, but the beneficial effects of propranolol urges for further investigation of this drug in the treatment of acute attacks. Only one case reports safe administration of other vasoactive substances like phenylephrine, isoproterenol, propranolol and phentolamine [111]. Furthermore, among the parasympathicolytics atropine is reported to be safe in porphyrinc patients, whereas isoprenaline should be used with caution [16, 18, 19, 28]. The antihypertensive agent clonidine is not recommended, or can only used with caution. For cardiac enhancement, atropine, dobutamine and dopamine have been classified as safe by the drug databases. There is only limited data available with respect to modern cardiovascular drugs like statins, angiotensin converting enzyme (ACE) inhbitors, angiotensin receptor antagonists, and calcium channel blockers. Limited data indicate that statins may precipitate porphyria cutanea tarda due to their HMG CoA reductase inhibiting properties [112, 113]. Lambrecht and coworkers showed that distinct antihypertensives induced slight increases in porphyrin accumulation, but nifedipine and enalapril both induced a significant rise in the porphyria content in chicken embryos [101]. The drug databases particularly define nifedipine and statins as unsafe to use in patients who have a porphyrinic constipation [18, 19]. Porphyria may be associated with renal failure and fluid retention, which might be treated by diuretic substances. Frusemide has been classified as safe by the European Porphyria Initiative, the South-African PDSD and the American Porphyria Foundation [17-19, 114, 115]. With respect to thiazides and spironolactone, there are contradictory indications in the literature. In particular, spironolactone has been reported as proporphyrinic drug in animal studies and has been classified as unsafe by the drug databases [116, 117].

Antibiotics Among the anti-infective agents, penicillin, amoxicillin-clavulinate and piperacillin-tazobactam are considered to be safe for porphyrinic patients. In the case of penicillin allergy, one may administer cephalosporins, aminoglycosides, clarithromycin, azithromycin, carbapenems and monobactams [19]. The antibiotics erythromycin, tetracycline, quinolones, sulphonamides and doxycycline should be avoided in porphyrinic patients, since they are highly associated with induction of acute crises [19, 118]. Furthermore, both metronidazole and tinidazole should be avoided in porphyrinic patients [19]. Summary of case reports We here reviewed all case reports as published by Pubmed between 2000 and 2008 that are related to anesthesia clinical practice. The case reports are represented in table 3. These case reports underline that in modern anesthesia, precipitation of a porphyrinic attack by perioperative agents can be avoided by using propofol, volatile anesthetics like sevoflurane or desflurane and morphinomimetics. However, a definition of the exact precipitation risk of each anesthetic can only be made after the performance of systemic clinical studies. Modern anti-porphyrinic strategies for the anesthesiologist Modern antiporphyrinic strategies by anesthesiologists should focus on 1) early recognition of the disease; 2) use of drugs with a low precipitation risk and 3) maintenance of perioperative hemodynamic, fluid and metabolic balance. Recognition of the disease and early prevention of an intermittent attack Anesthesiologists may encounter patients with a known porphyrinic condition and should consider careful revision of the drug medication as used by these patients. Furthermore, prior to surgery, blood or urine sample testing should be performed in order to determine the level of porphyrin accumulation as indicator of the disease activity. In the case of elevated porphyrin levels, anesthesiologists may consider the use of hemin in order to prevent further progression of the disease. In the case of de novo patients, early recognition is of importance for postoperative patient outcome.

Usage of drugs with low precipitation risks In patients with a known porphyrinic condition the anesthesiologist should consider to prevent precipitation of an attack by intraoperatively used drugs, for instance by prophylactic hemin administration. Porphyria associated hypertension and tachycardia may be prevented by preoperative use of propranolol. Furthermore, in the preoperative phase benzodiazepines may be safely used to reduce anxiety. Fortunately, modern anesthesia allows a combination of drugs that can be used to induce and maintain anesthesia. Induction by propofol, in combination with anesthetic maintenance by inhalational anesthetics like sevoflurane and desflurane may be safely used in these patients. Furthermore, short-term administration of muscular relaxantia like rocuronium is not contraindicated for porphyrinic patients. Analgesia may be induced by usage of fentanyl or morphine, and additionally locoregional spinal techniques may be applied. Postoperatively, fluid and metabolic balance should be tightly controlled, since precipitation of a porphyrinic attack may induce renal failure and hyponatremia, sometimes followed by neuromuscular pain and seizures. Maintenance of perioperative hemodynamic, fluid and metabolic balance Fasting patients may receive a prophylactic infusion of saline-glucose in order to prevent dehydration, hyponatremia and hypoglycemia in the occurrence of a porphyrinic attack. A tightly controlled fluid balance may be helpful in the diagnosis of early signs of porphyria, since these signs may be associated with impaired renal function.

Conclusion There are several case reports published that confirmed the possibility to provide safe perioperative management in patients with a porphyrinic condition. Improved biochemical and analysis techniques allow early detection of novel patients and the induction of an acute porphyrinic episode. The rarity of the disease however prohibits systemic investigation of the risk of induction of the disease by anesthetics. Unexpected and uncontrolled events, like alcohol abuse, hormonal fluctuations or stress may still open Pandora’s box in modern perioperative care.


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references 1. James M.F.M. and Hift R.J. Porphyrias. Br J Anaesth 2000; 85: 143-153. 2. Hoppe-Seyler F. Das Hämatin. Tubinger Med-Chem Untersuch 1871; 4: 523–533. 3. Stokvis B.J. Over twee zeldzame kleurstoffen in urine van zieken. Ned Tijdschr Geneesk 1889; 2: 409-417. 4. Ajioka R.S., Phillips J.D., Kushner J.P. Biosynthesis of heme in mammals. Biochim Biophys Acta 2006; 1763: 723-736. 5. Jeans J.B., Savik K., Gross C.R., Weimer M.K., Bossenmaier I.C., Pierach C.A., Bloomer J.R. Mortality in patients with acute intermittent porphyria requiring hospitalization: a United States case series. Am J Med Genet 1996; 65: 269-273. 6. Jordan P.M., Dailey H.I. Biochemistry of porphyrins. Mol Aspects Med 1990; 11: 21–37. 7. Kauppinen R. Porphyrias. Lancet 2005; 365: 241-252. 8. Moore M.R., McColl K.E., Rimington C., Goldberg A. Disorders of porphyrin metabolism. New York: Plenum Publishing Corporation, 1987. 9. Thadani H., Deacon A., Peters T. Diagnosis and management of porphyria. BMJ 2000; 320: 1647-1651. 10. Tschudy D.P. Biochemical lesions in porphyria. JAMA 1965; 191: 718-730. 11. Thunell S., Harper P., Brock A., Petersen N.E. Porphyrins, porphyrin metabolism and porphyrias. II. Diagnosis and monitoring in the acute porphyrias. Scand J Clin Lab Invest 2000; 60: 541-559. 12. Thunell S., Harper P. Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda--suggestions for a handling programme. Scand J Clin Lab Invest 2000; 60: 561-579. 13. Deybach J.C., Badminton M., Puy H., Sandberg S., Frank J., Harper P., Martasek P., Minder E., Parker S., Thunell S., Elder G. European porphyria initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field. Physiol Res 2006; 55: 67-73. 14. Disler P.B., Eales L. The acute attack of porphyria. S Afr Med J 1982; 61: 82-84. 15. Caron S., Berton J., Beydon L. Quality of anaesthesia-related information accessed via Internet searches. Br J Anaesth 2007; 99: 195-201. 16. American Porphyria Foundation. http://www.porphyriafoundation. com 2007. 17. Australian National Research Centre for Environmental Toxicology. www.uq.edu.au/porphyria/ 2007. 18. European Porphyria Initiative steering group. http://www.porphyriaeurope.org. 2007. 19. Porphyria Drug Safety Database (PDSD), Porphyria South Africa. www.porphyria.uct.ac.za 2007. 20. Anderson K.E., Bloomer J.R., Bonkovsky H.L., Kushner J.P.,

Pierach C.A., Pimstone N.R., Desnick R.J. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005; 142: 439-450. 21. Anderson K.E. Effects of antihypertensive drugs on hepatic heme biosynthesis, and evaluation of ferrochelatase inhibitors to simplify testing of drugs for heme pathway induction. Biochim Biophys Acta 1978; 543: 313-327. 22. Minder E.I., Gouya L., SchneiderYin X., Deybach J.C. A genotypephenotype correlation between null-allele mutations in the ferrochelate gene and liver complication in patients with erythropoietic protoporphyria. Cell Mol Biol 2002; 48: 91-96. 23. Von und zu Fraunberg M., Timonen K., Mustajoki P., Kauppinen R. Clinical and biochemical characteristics and genotype-phenotype correlation in Finnish variegate porphyria patients. Eur J Hum Genet 2002; 10: 649-657. 24. Wiman A., Floderus Y., Harper P. Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoetic protoporphyria. J Hum Genet 2003; 48: 70-76. 25. Fraunberg M., Pischik E., Udd I., Kauppinen R. Clinical and biochemical characteristics and genotypephenotype correlation in 143 Finnish and Russian patients with acute intermittent porphyria. Medicine (Baltimore) 2005; 84: 35-47. 26. Thunell S., Floderus Y., Henrichson A., Harper P. Porphyria in Sweden. Physiol Res 2006; 55: 109-118. 27. Taddeini L., Watson C.J. The clinical porphyrias. Semin Hematol 1968; 5: 335-369. 28. Jensen N.F., Fiddler D.S., Strieper V. Anesthetic considerations in porphyrias. Anesth Analg 1995; 80: 591-599. 29. Rigal J.C., Blanloeil Y. Anaesthesia and porphyria. Min Anest 2002; 68: 326-331. 30. Herrick AL, McColl KE. Acute intermittent porphyria. Best Pract Res Clin Gastroenterol 2005; 19: 235-249. 31. Hift R.J. The diagnosis of porphyria. S Afr Med J 1999; 89: 611-614. 32. Pierach C.A., Watson C.J. Treatment of acute hepatic porphyria. Lancet 1978; 1: 1361-1362. 33. Hift R.J., Meissner P.N. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore) 2005; 84: 48-60. 34. Alla V., Bonkovsky H.L. Iron in nonhemochromatotic liver disorders. Semin Liver Dis 2005; 25: 461-472. 35. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol 2006; 135: 281-292. 36. Meyer U.A., Schuurmans M.M., Lindberg R.L. Acute porphyrias: pathogenesis of neurological mani-

festations. Semin Liver Dis 1998; 18: 43-52. 37. Sima A.A., Kennedy J.C., Blakeslee D., Robertson D.M. Experimental porphyric neuropathy: a preliminary report. Can J Neurol Sci 1981; 8: 105113. 38. Lim H.W. Mechanisms of phototoxicity in porphyria cutanea tarda and erythropoietic protoporphyria. Immunol Ser 1989; 46: 671-685. 39. Thunell S., Harper P., Brun A. Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythyropoietic protoporphyria-diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest 2000; 60: 581-604. 40. Wahlin S., Floderus Y., Ros A.M., Broome U., Harper P. The difficult clinical diagnosis of erythropoietic protoporphyria. Physiol Res 2006; 55: 155-157. 41. Crook M.A. Clinical chemistry and Metabolic Medicine, London: Hodder Arnold, 2006. 42. Periasamy V., al Shubaili A., Girsh Y. Diagnostic dilemmas in acute intermittent porphyria. A case report. Med Princ Pract 2002; 11: 108-111. 43. Church S.E., McColl K.E., Moore M.R., Youngs G.R. Hypertension and renal impairment as complications of acute porphyria. Nephrol Dial Transplant 1992; 7: 986-990. 44. Eales L., Dowdle E.B. Electrolyte abnormalities in porphyria. Lancet 1969; 1: 51. 45. Bonkowsky H.L., Tschudy D.P., Collins A., Doherty J., Bossenmaier I., Cardinal R., Watson C.J. Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin. Proc Natl Acad Sci USA 1971; 68: 2725-2729. 46. Anderson K.E., Collins S. Open-label study of hemin for acute porphyria: clinical practice implications. Am J Med 2006; 119: 19-24. 47. Herrick A.L., McColl K.E., Moore M.R., Cook A., Goldberg A. Controlled trial of haem arginate in acute hepatic porphyria. Lancet 1989; 1: 1295-1297. 48. Eefsen M., Rasmussen A., Wulf H.C., Brock A., Hansen B.A. Erythropoietic protoporphyria and pretransplantation treatment with nonbiological liver assist devices. Liver Transpl 2007; 13: 655-667. 49. Medenica R., Lazovic G., Long P., Corbitt W., Powell D. Plasmapheresis combined with somatostatin is a successful treatment of porphyrias. Ther Apher 1997; 1: 159-164. 50. Miyauchi S., Shiraishi S., Miki Y. Small volume plasmapheresis in the management of porphyria cutanea tarda. Arch Dermatol 1983; 119: 752-755. 51. Sita D., Maurri S., Groppi C., Barontini F. Possible effectiveness of plasmapheresis on the neurological complications in a case of acute intermittent porphyria. Ital J Neurol Sci 1984; 5: 299-302.

52. Sardh E., Rejkjaer L., Andersson D.E., Harper P. Safety, pharmacokinetics and pharmacodynamics of recombinant human porphobilinogen deaminase in healthy subjects and asymptomatic carriers of the acute intermittent porphyria gene who have increased porphyrin precursor excretion. Clin Pharmacokinet 2007; 46: 335-349. 53. de Verneuil H., Ged C., Boulechfar S., Moreau-Gaudry F. Porphyrias: animal models and prospects for cellular and gene therapy. J Bionerg Biomembr 1995; 27: 239-248. 54. Yasuda M., Domaradzki M.E., Armentano D. et al. Acute intermittent porphyria: vector optimization for gene therapy. J Gene Med 2007; 9: 806-811. 55. Bonkowsky H.L., Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis 1982; 2: 108-124. 56. Lambrecht R.W., Gildemeister O.S., Pepe J.A., Tortorelli K.D., Williams A., Bonkovsky H.L. Effects of antidepressants and benzodiazepinetype anxiolytic agents on hepatic porphyrin accumulation in primary cultures of chick embryo liver cells. J Pharmacol Exp Ther 1999; 291: 11501155. 57. Badminton M.N., Elder G.H. Management of acute and cutaneous porphyrias. Int J Clin Pract 2002; 56: 272-278. 58. Durmus M., Turkoz A., Togal T., Koroglu A., Toprak H.I., Ersoy M.O. Remifentanil and acute intermittent porphyria. Eur J Anaesthesiol 2002; 19: 839-40. 59. Kantor G., Rolbin S.H. Acute intermittent porphyria and caesarean delivery. Can J Anaesth 1992; 39: 282-285. 60. Consolo D., Ouardirhi Y., Wessels C., Girard C. Obstetrical anaesthesia and porphyrias. Ann Fr Anesth Reanim 2005; 24: 428-431. 61. Testa B., Kramer S.D. The biochemistry of drug metabolism--an introduction: part 1. Principles and overview. Chem Biodivers 2006; 3: 1053-1101. 62. Testa B., Kramer S.D. The biochemistry of drug metabolism--an introduction: Part 2. Redox reactions and their enzymes. Chem Biodivers 2007; 4: 257-405. 63. Berthoud M.C., Reilly C.S. Adverse effects of general anaesthetics. Drug Saf 1992; 7: 434-459. 64. Gorchein A. Drug treatment in acute porphyria. Br J Clin Pharmacol 1997; 44: 427-434. 65. Allende I. Paula. New York:Harper Collins Publishers, 2005. 66. Ashley E.M. Anaesthesia for porphyria. Br J Hosp Med 1996; 56: 37-42. 67. Disler P.B., Moore M.R. Drug therapy in the acute porphyrias. Clin Dermatol 1985; 3: 112-124. 68. Dover S.B., Plenderleith L., Moore M.R., McColl K.E. Safety of general anaesthesia and surgery in acute

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hepatic porphyria. Gut 1994; 35: 11121115. 69. Eales L., Linder G.C. Porphyria-the acute attack: analysis of 80 cases. S Afr Med J 1962; 36: 284-292. 70. Ward R.J. Porphyria and its relation to anesthesia. Anesthesiology 1965; 26: 212-215. 71. Johansson A., Moller C., Fogh J., Harper P. Biochemical characterization of porphobilinogen deaminasedeficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement. Mol Med 2003; 9: 193-199. 72. Tishler P.V. The effect of therapeutic drugs and other pharmacologic agents on activity of porphobilinogen deaminase, the enzyme that is deficient in intermittent acute porphyria. Life Sci 1999; 65: 207-214. 73. Harrison G.G., Meisner P.N., Hift R.J. Anaesthesia for the porphyric patient. Anaesthesia 1993; 48: 417-421. 74. Tidmarsh M.D. Porphyria, propofol and rats. Br J Anaesth 1996; 76: 171172. 75. Meissner P.N., Harrison G.G., Hift R.J. Propofol as an i.v. anaesthetic induction agent in variegate porphyria. Br J Anaesth 1991; 66: 60-65. 76. Asirvatham S.J., Johnson T.W., Oberoi M.P., Jackman W.M. Prolonged loss of consciousness and elevated porphyrins following propofol anesthesia. Anesthesiology 1998; 89: 1029-1031. 77. Elcock D., Norris A. Elevated porphyrins following propofol anaesthesia in acute intermittent porphyria. Anaesthesia 1994; 49: 957958. 78. Pandey C.K., Singh N., Bose N., Sahay S. Gabapentin and propofol for treatment of status epilepticus in acute intermittent porphyria. J Postgrad Med 2003; 49: 285. 79. Baratto F., Meggiolaro M. Anesthesia with propofol and atracurium in a case of porphyria cutanea tarda. Minerva Anestesiol 1998; 64: 535-539. 80. Hiraki T., Oishi K., Kano T. Anesthetic management of a patient with a history of acute intermittent porphyria and an elevation of urinary porphobilinogen. Masui 2001; 50: 882-885. 81. Pazvanska E.E., Hinkov O.D., Stojnovska L.V. Uneventful propofol anaesthesia in a patient with acute intermittent porphyria. Eur J Anaesthesiol 1999; 16: 485-492. 82. Sarantopoulos C.D., Bratanow N.C., Stowe D.F., Kampine J.P. Uneventful propofol anesthesia in a patient with coexisting hereditary coproporphyria and hereditary angioneurotic edema. Anesthesiology 2000; 92: 607-609. 83. Harrison G.G., Moore M.R., Meissner P.N. Porphyrinogenicity of etomidate and ketamine as continious infusions. Br J Anaesth 1985; 57: 420-423. 84. Kostrzewska E., Gregor A., Lipinska D. Ketamine in acute intermittant

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porphyria-dangerous or safe? Anesthesiology 1979; 51:184. 85. Rizk S.F. Ketamine is safe in acute intermittant porphyria. Anesthesiology 1979; 51: 184. 86. Rizk S.F., Jacobson J.H., Silvay G. Ketamine as an induction agent for acute intermittant porphyria. Anesthesiology 1977; 46: 305-306. 87. Silvay G., Miller R., Tausk C.: Safety of ketamine in patients with acute intermittent porphyria. Acta Anaesth Scand 1979; 23: 329-330. 88. Buzaleh A.M., Garcia-Bravo M., Navarro S., Moran-Jimenez M.J., Mendez M., Batlle A., Fontanellas A., de Salamanca R.E. Volatile anaesthetics induce biochemical alterations in the heme pathway in a B-lymphocyte cell line established from hepatoerythropoietic porphyria patients (LBHEP) and in mice inoculated with LBHEP cells. Int J Biochem Cell Biol 2004; 36: 216-222. 89. Evans P.R., Graham S., Kumar C.M. The use of sevoflurane in acute intermittent porphyria. Anaesthesia 2001; 56: 388-389. 90. Hsieh C.H., Hung P.C., Chien C.T., Shih Y.R., Peng S.K., Luk H.N., Tsai T.C. The use of rocuronium and sevoflurane in acute intermittent porphyria - a case report. Acta Anaesthesiol Taiwan 2006; 44: 169-171. 91. Takahashi S., Shiraishi Y., Yokoyama J. A case report of rapid inhalation induction with sevoflurane in a patient with porphyria. Masui 2005; 54: 1292-1294. 92. Messmer M., Gerheuser F., Forst H. Desflurane in acute intermittent porphyria. Anaesthesist 2004; 53: 244-248. 93. Sheppard L., Dorman T. Anesthesia in a child with homozygous porphobilinogen deaminase deficiency: a severe form of acute intermittent porphyria. Paediatr Anaesth 2005;15: 426-428. 94. Jackson S.H. Hereditary Hepatic Porphyrias. In: Katz J, Benumof JL, Kadis LB, eds. Anesthesia and Uncommon Diseases. Philadelphia: W.B. Saunders, 1990; 84-99. 95. Bohrer H., Schmidt H. Regional anesthesia as anesthetic technique of choice in acute hepatic porphyria. J Clin Anesth 1992; 4: 259. 96. McNeill M.J., Bennet A. Use of regional anaesthesia in a patient with acute porphyria. Br J Anaesth 1990; 64: 371-373. 97. Campos J.H., Stein D.K., Michel M.K., Moyers J.R. Anesthesia for aortic valve replacement in a patient with acute intermittent porphyria. J Cardiothorac Vasc Anesth 1991; 5: 258-261. 98. Sneyd J.R., Kreimer-Birnbaum M., Lust M.R., Heflin J. Use of sufentanil and atracurium anesthesia in a patient with acute porphyria undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth 1995; 9: 757-758. 99. LaDuca J.R., Bouman P.H., Gaspari A.A. Nonsteroidal antiinflammatory

drug-induced pseudoporphyria: a case series. J Cutan Med Surg 2002; 6: 320-326. 100. Shenhav S., Gemer O., Sassoon E., Segal S. Acute intermittent porphyria precipitated by hyperemesis and metoclopramide treatment in pregnancy. Acta Obstet Gynecol Scand 1997; 76: 484-485. 101. Lambrecht R.W., Gildemeister O.S., Williams A., Pepe J.A. et all. Effects of selected antihypertensives and analgesics on hepatic porphyrin accumulation: implications for clinical porphyria. Biochem Pharmacol 1999; 58: 887-896. 102. Moore M.R. International review of drugs in acute porphyrias-1980. Int J Biochem 1980; 12: 1089-1097. 103. Freedman M., Ingram H.J., Smuts J.H.L. Midazolam for the induction of anesthesia in patients with porphyria. S Afr Med J 1985; 68: 212. 104. Lin Y.C., Chen L. Atracurium in a patient with acute intermittent porphyria. Anesth Analg 1990; 71: 440-441. 105. McLouglin C. Use of propofol in a patient with porphyria. Br J Anaesth 1989; 62: 114. 106. Beal M.F., Atuk N.O., Westfall T.C., Turner S.M. Catecholamine uptake, accumulation, and release in acute porphyria. J Clin Invest 197; 60: 1141-1148. 107. Bravenboer B., Erkelens D.W. Acute hypertension mimicking phaeochromocytoma as main presenting feature of acute intermittent porphyria. Lancet 1989; 2: 928. 108. Lithner F. Could attacks of abdominal pain in cases of acute intermittent porphyria be due to intestinal angina? J Int Med 2000; 247: 407409. 109. Epstein O., Schoenfeld N., Greenblat Y., Lahav M., Atsmon A. The influence of propranolol on the concentration of heme and on the activity of delta aminolevulinate synthase in monolayers of chick embryo liver cells. Biochem Pharmacol 1982; 31: 485-459. 110. Schoenfeld N., Mamet R., Mevasser R., Atsmon A. Experimental latent and acute porphyria in the nonfasted rat; preventive effect of propranolol. Scand J Clin Lab Invest 1991; 51: 667-673. 111. Goto J., Inoue K., Mannen T. Autonomic dysfunctions in acute intermittent porphyria. Rinsho Shinkeigaku 1989; 29: 774-777. 112. Perrot J.L., Guy C., Bour Guichenez G., Amigues O., Servoz J., Cambazard F. Porphyria cutanea tarda induced by HMG CoA reductase inhibitors: simvastatin, pravastatin. Ann Dermatol Venereol 1994; 121: 817-819. 113. Schindl A., Trautinger F., Pernerstorfer-Schon H., Konnaris C., Honigsmann H. Porphyria cutanea tarda induced by the use of pravastatin. Arch Dermatol 1998; 134: 1305-1306. 114. Lopez Montes A., Lorenzo I., Perez Martinez J. Porphyria and inap-

propriate antidiuretic hormone syndrome. Nefrologia 2004; 24: 85-88. 115. Breier F., Feldmann R., Pelzl M., Gschnait F. Pseudoporphyria cutanea tarda induced by furosemide in a patient undergoing peritoneal dialysis. Dermatology 1998; 197: 271273. 116. Anderson K.E., Sassa S., Bishop D.F., Desnick R.J. Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Scriver CR, Beaudet A, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001; 2991-3062. 117. Lim C.K., Danton M., Clothier B., Smith A.G. Dihydroxy-, hydroxyspirolactone-, and dihydroxyspirolactone-urochlorins induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the liver of mice. Chem Res Toxicol 2006; 19: 1660-1667. 118. Parish L.C. Newer concepts in antimicrobial therapy. Adv Exp Med Biol 1999; 455: 397-406. 119. Rassiat E., Ragonnet D., Barriere E., Soupison A., Bernard P. Acute intermittent porphyria revealed by a paradoxical reaction to a benzodiazepine. Gastroenterol Clin Biol 2001; 25: 832. 120. Mseddi M.A., Frikha M.F., Affes N., Zouari R., Abbes I., Ben Amar M., Beyrouti M.I. Fatal postoperative crisis in acute hereditary porphyria. Tunis Med 2002; 80: 288-291. 121. Maerker J.M., Harm A., Foeldvari I., Hoger P.H. Naproxen-induced pseudoporphyria. Hautarzt 2001; 52: 1026-1029. 122. Antony F., Layton A.M. Nabumetone-associated pseudoporphyria. Br J Dermatol 2000; 142: 1067-1069. 123. Schad S.G., Hamm H., Girschick H.J. Bullae, erosions and scars in the face of 2 girls with idiopathic arthritis. Naproxen-induced pseudoporphyria. Hautarzt 2002; 53: 51-53. 124. O’Donoghue N.B., Higgins E.M. Case 1: Naproxen-induced pseudoporphyria. Clin Exp Dermatol 2002; 27: 339-40. 125. Markus R., Reddick M.E., Rubenstein M.C. Rofecoxib-induced pseudoporphyria. J Am Acad Dermatol 2004; 50: 647-648. 126. Phung T.L., Pipkin C.A., Tahan S.R., Chiu D.S. Beta-lactam antibioticinduced pseudoporphyria. J Am Acad Dermatol 2004; 51: 80-82. 127. DeGiovanni C.V., Darley C.R. Pseudoporphyria occurring during a course of ciprofloxacin. Clin Exp Dermatol 2008; 33: 109-110. 128. Kwong W.T., Hsu S. Pseudoporphria associated with voriconazole. J Drugs Dermatol 2007; 6: 1042-1044.

Advertentie Verkorte productinformatie Bridion 100 mg/ml oplossing voor injectie Samenstelling: 1 ml Bridion 100mg/ml, oplossing voor injectie, bevat sugammadex als natriumzout equivalent aan 100 mg sugammadex. Elke ml bevat 9,7 mg natrium. Indicatie: Opheffing van de door rocuronium of vecuronium geïnduceerde neuromusculaire blokkade. Bij kinderen en adolescenten wordt het gebruik van sugammadex alleen aanbevolen bij standaardopheffing van een door rocuronium geïnduceerde neuromusculaire blokkade. Dosering: Sugammadex dient intraveneus te worden toegediend als eenmalige bolusinjectie. Sugammadex mag alleen worden toegediend door of onder supervisie van een anesthesist. Het gebruik van een geschikte neuromusculaire monitortechniek wordt aanbevolen om het herstel van de neuromusculaire blokkade te bewaken. De aanbevolen dosis sugammadex is afhankelijk van het niveau van de neuromusculaire blokkade. De aanbevolen dosis is niet afhankelijk van de toegediende anesthesie. Bridion kan worden verdund tot 10 mg/ml ten behoeve van een betere nauwkeurigheid van de dosering bij kinderen (zie rubriek 6.6*). Standaardopheffing: Er wordt een dosis van 4 mg/kg sugammadex aanbevolen indien het herstel ten minste 1-2 posttetanische tellingen (PTC) heeft bereikt na een door rocuronium of vecuronium geïnduceerde blokkade. Een dosis van 2 mg/kg sugammadex wordt aanbevolen als spontaan herstel is opgetreden tot minimaal het terugkeren van T2 na een door rocuronium of vecuronium geïnduceerde blokkade. Bij kinderen en adolescenten (2 17 jaar) wordt voor standaardopheffing bij terugkeer van T2 na een door rocuronium geïnduceerde blokkade 2 mg/ kg sugammadex aanbevolen. Andere situaties van standaardopheffing bij kinderen en adolescenten zijn niet onderzocht en worden daarom niet aanbevolen. Het gebruik van sugammadex bij voldragen pasgeborenen en zuigelingen wordt niet aanbevolen. Onmiddellijke opheffing: Als er klinische noodzaak bestaat van onmiddellijke opheffing na toediening van rocuronium, wordt een dosis van 16 mg/kg sugammadex aanbevolen. Onmiddellijke opheffing is bij kinderen en adolescenten niet onderzocht en wordt daarom niet aanbevolen. Hernieuwde toediening sugammadex: In de uitzonderlijke situatie dat zich postoperatief, na een initiële dosis van 2 mg/ kg of 4 mg/kg, opnieuw een blokkade voordoet (zie rubriek 4.4*), wordt een herhalingsdosis van 4 mg/kg sugammadex aanbevolen. Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel of voor één van de hulpstoffen. Waarschuwingen: Patiënten moeten kunstmatig worden beademd totdat de spontane ademhaling voldoende is hersteld. Andere geneesmiddelen, die tijdens en na de operatie zijn gebruikt, kunnen de ademhalingsfunctie onderdrukken. In geval dat hernieuwd optreden van een neuromusculaire blokkade wordt waargenomen, kunnen kunstmatige beademing en hernieuwde toediening van sugammadex noodzakelijk zijn (zie rubriek 4.2*). Om hernieuwd optreden van neuromusculaire blokkade te voorkomen, dienen de aanbevolen doses van sugammadex te worden gebruikt. Een verhoogd risico op bloedingen kan niet worden uitgesloten bij patiënten: met erfelijke vitamine K afhankelijke stollingsfactorgerelateerde deficiënties; met reeds bestaande coagulopathiën; die coumarinederivaten gebruiken en met een INR boven 3,5; die antistollingsmiddelen gebruiken en een dosis van 16 mg/kg sugammadex ontvangen. Sugammadex mag niet worden gebruikt voor opheffing van blokkades geïnduceerd door niet steroïde neuromusculair blokkerende stoffen en door steroïde neuromusculair blokkerende stoffen, anders dan rocuronium of vecuronium. Indien de neuromusculaire blokkade wordt opgeheven onder voortzetting van de anesthesie, dienen aanvullende doses van het anestheticum en/of opioïd te worden gegeven op geleide van de klinische indicatie. Indien hernieuwde neuromusculaire blokkade is vereist vóór het verstrijken van de aanbevolen wachttijd van 24 uur, dient een niet-steroïde neuromusculair blokkerende stof te worden gebruikt. Sugammadex is niet onderzocht bij patiënten, die rocuronium of vecuronium krijgen op de Intensive Care. Mogelijke interacties: In situaties waar mogelijke verdringingsinteracties verwacht kunnen worden, dienen patiënten (na parenterale toediening van een ander geneesmiddel binnen 6 uur na toediening van sugammadex) zorgvuldig gecontroleerd te worden op tekenen van hernieuwd optreden van een blokkade (voor maximaal ongeveer 15 minuten). In situaties waar mogelijke bindingsinteracties kunnen optreden wordt de arts geadviseerd om het geneesmiddel opnieuw toe te dienen of de toediening van een therapeutisch gelijkwaardig geneesmiddel en/of niet farmacologische interventies te overwegen (zie rubriek 4.5*). Nierfunctiestoornis: Het gebruik van sugammadex bij patiënten met een ernstige nierfunctiestoornis wordt niet aanbevolen. Leverfunctiestoornis: Patiënten met een ernstige leverfunctiestoornis moeten met grote voorzichtigheid worden behandeld. Vertraagd herstel: Aandoeningen waarbij sprake is van een verlengde circulatietijd, zoals cardiovasculaire aandoeningen, gevorderde leeftijd of oedeemvorming kunnen gepaard gaan met langere hersteltijden. Allergische reacties: Artsen moeten voorbereid zijn op de mogelijkheid van allergische reacties en de nodige voorzorgsmaatregelen treffen. Natriumbeperkt dieet: Indien er meer dan 2,4 ml oplossing moet worden toegediend, dient hier rekening mee te worden gehouden bij patiënten met een natriumbeperkt dieet. Verlenging van het QTc-interval: De routinematige voorzorgsmaatregelen voor de behandeling van aritmie moeten in overweging worden genomen. Pediatrische populatie: De interacties en waarschuwingen voor volwassenen gelden ook voor kinderen. Interacties: Voor toremifeen kunnen verdringingsinteracties niet worden uitgesloten. Het gebruik van fusidinezuur in de preoperatieve fase kan het herstel van de T4/T1 ratio tot 0,9 enigszins vertragen. Voor hormonale anticonceptiva kon een klinisch relevante bindingsinteractie niet worden uitgesloten. In het algemeen interfereert sugammadex niet met laboratoriumtests, met als mogelijke uitzondering de progesteronbepaling in serum. Doseringen van 4 mg/kg en 16 mg/kg sugammadex kunnen de geactiveerde partiële tromboplastinetijd (aPTT) en protrombinetijd (PT) voor korte duur (< 30 minuten) licht verlengen. Bijwerkingen: De veiligheid van sugammadex is beoordeeld op basis van een geïntegreerde veiligheidsdatabase van ongeveer 1700 patiënten en 120 vrijwilligers. Zeer vaak: Dysgeusie (metalen of bittere smaak), werd vooral waargenomen na doses van 32 mg/kg sugammadex of hoger. Vaak: Complicaties bij anesthesie, indicatief voor herstel van neuromusculaire functie. Soms: In een paar gevallen zijn allergieachtige reacties (bijv. bloedstuwing, erythemateuze huiduitslag) gerapporteerd na gebruik van sugammadex waarvan er een als milde allergische reactie is bevestigd. Na behandeling met sugammadex zijn enkele gevallen van awareness gerapporteerd. Hernieuwd optreden van een blokkade: De incidentie van het hernieuwd optreden van een blokkade was 2% na gebruik van sugammadex en 0% in de placebogroep. Vrijwel al deze gevallen kwamen voor in dose finding onderzoeken met suboptimale doses (minder dan 2 mg/kg) (zie rubriek 4.4*). Longpatiënten: Net als bij alle patiënten met een voorgeschiedenis van longcomplicaties, dient de arts zich bewust te zijn van het mogelijke optreden van bronchospasmen. Houder van de vergunning voor het in de handel brengen: N.V. Organon, Kloosterstraat 6, 5349 AB Oss, Nederland. Nummers van de vergunning voor het in de handel brengen: EU/1/08/466/001-2 Afleverstatus: U.R. Datum van eerste verlening van de vergunning: 25 juli 2008. Datum van wijziging van de (verkorte) productinformatie: 2 juni 2010 * Voor de volledige productinformatie verwijzen wij naar de huidig goedgekeurde SPC.

Zeker Zaldiar

100727 Bridion bijsluiter zww1.indd 1

Samenstelling: Elke QUTENZA-huidpleister bevat 179 mg capsaïcine (640 μg/cm2, 8% g/g). Elke tube reinigingsgel (50 g) bevat 0,2 mg/g butylhydroxyanisol (E320). Therapeutische indicatie: QUTENZA is geïndiceerd voor de behandeling van perifere neuropathische pijn bij niet-diabetische volwassenen, als monotherapie of in combinatie met andere analgetica. Dosering en wijze van toepassing: QUTENZA dient door een beroepsbeoefenaar te worden toegediend. Het behandelgebied, dient vóór het aanbrengen van QUTENZA met een lokaal anaestheticum te worden voorbehandeld. Er mogen maximaal vier pleisters worden gebruikt. QUTENZA dient op intacte, niet-geïrriteerde, droge huid te worden aangebracht gedurende 30 minuten op de voeten en op andere plaatsen 60 minuten. Behandeling met QUTENZA kan elke 3 maanden worden herhaald, afhankelijk van de persistentie of terugkeer van de pijn. Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel of voor één van de hulpstoffen. Niet gebruiken: Indien de patiënt allergisch (overgevoelig) is voor capsaïcine, chilipepers of één van de andere bestanddelen. QUTENZA mag op geen enkel deel van het hoofd of het gezicht van patiënten worden gebruikt. QUTENZA niet op beschadigde huid gebruiken. QUTENZA of andere materialen die met behandelde gebieden in contact zijn geweest niet aanraken, omdat dit een branderig en prikkend gevoel kan veroorzaken. Ogen, mond of andere gevoelige gebieden niet aanraken. Snuiven of inademen dicht bij de QUTENZA-huidpleister kan hoesten en niezen veroorzaken. Bijwerkingen: De volgende bijwerkingen kunnen optreden op de aanbrengplaats: Zeer vaak (≥ 1/10): pijn en erytheem; Vaak (≥ 1/100, < 1/10) pruritus, papels, vesikels, oedeem, zwelling en droogheid. De bijwerkingen waren van voorbijgaande aard en waren meestal licht tot matig van ernst. Verder kwamen Soms (≥ 1/1000 en < 1/100) voor dysgeusie, hypo-esthesie, branderig gevoel, herpes zoster, oogirritatie, eerstegraads atrioventriculair (AV-)blok, tachycardie, palpitaties, hypertensie, hoesten, keelirritatie, misselijkheid, pijn in extremiteit en spierspasmen. De reinigingsgel voor QUTENZA kan lokale huidreacties (bijv. contacteczeem) of irritatie van de ogen en slijmvliezen veroorzaken. Voorzorgsmaatregelen voor gebruik: Altijd nitrilhandschoenen dragen bij het hanteren van QUTENZA en het reinigen van behandelde gebieden. Wettelijke categorie: Uitsluitend receptgeneesmiddel. Aard en inhoud van de verpakking: Set van sachet met 1 QUTENZA-huidpleister en 1 tube reinigingsgel in een kartonnen doos. Datum laatste wijziging IB-tekst: 25 september 2009. Volledige productinformatie is op aanvraag verkrijgbaar bij: Astellas Pharma B.V., Postbus 108, 2350 AC Leiderdorp Tel.: (071) 5455 854, Fax: (071) 5455 850. Referenties: [1] SPC QUTENZA. Astellas Pharma BV. September 2009 [2] Backonja M et al., Lancet Neurol 2008; 7(12):1106-1112. Erratum in: Lancet Neurol 2009 Jan; 8(1):31 [3] Simpson DM et al., Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008; 70(24):2305-2313.

Referenties: 1. Van Seventer R, et al. Current Medical Research and Opinion 2006; 22:375-384. 2. Dworkin RH, et al. Neurology 2003; 60:1274-1283. 3. Sabatowski R, et al. Pain 2004; 109:26-35. 4. Rosenstock J, et al. Pain 2004; 110:628-638. 5. Irving GA. Neurology 2005; 64 (suppl 3):S21-S27. Verkorte productinformatie Lyrica (oktober 2010) Samenstelling: Lyrica 25, 75, 150 en 300 mg harde capsules bevatten respectievelijk 25, 75, 150 27-07-10 13:33 en 300 mg pregabaline. Indicaties: Behandeling van perifere en centrale neuropathische pijn bij volwassenen, adjuvant-therapie bij volwassenen met 255/QUT - IBpartiële 90x130mm.indd 14-10-2010 12:28:1 epilepsie met of zonder 1 secundaire gegeneraliseerde aanvallen en behandeling van gegeneraliseerde angststoornis (GAS) bij volwassenen.

Referenties: 1. Registratietekst Zaldiar. 2. Emkey R et al. J Rheumatol. 2004; 31(1): 150-156. 3. Rosenthal et al. J Am Geriatr Soc. 2004 Mar;52(3): 374-380. 4. Silverfield et al. Clin Ther. 2002 Feb;24(2):282-297.

ZLD-ADV-20110104-01

Verkorte Productinformatie Zaldiar® / Zaldiar® Bruis 37,5 mg/325 mg Samenstelling: ZALDIAR filmomhulde tabletten en ZALDIAR BRUIS bruistabletten bevatten 37,5 mg tramadol en 325 mg paracetamol. Indicaties: ZALDIAR en ZALDIAR BRUIS zijn bestemd voor de symptomatische behandeling van matige tot ernstige pijn. Dosering: Het wordt aanbevolen de behandeling te starten met twee (bruis)tabletten, maximale dosering per dag is acht (bruis)tabletten (overeenkomend met 300 mg tramadol en 2600 mg paracetamol). ZALDIAR en ZALDIAR BRUIS worden niet aanbevolen bij kinderen jonger dan 12 jaar. Contra-indicaties: Overgevoeligheid voor tramadol, paracetamol of voor één van de hulpstoffen. Acute intoxicatie met alcohol, hypnotica, centraal werkende analgetica, opioïden of psychotrope middelen. Gebruik van MAO-remmers, ernstige leverfunctiestoornissen, epilepsie die niet voldoende onder controle is door middel van behandeling. Speciale waarschuwingen: ZALDIAR en ZALDIAR BRUIS worden niet aanbevolen bij patiënten met ernstige nierinsufficiëntie (creatinineklaring < 10 ml/min) of bij ernstige ademhalingsinsufficiënte. Niet gelijktijdig gebruiken met andere paracetamol of tramadol bevattende geneesmiddelen zonder een arts te raadplegen. Epilepsiepatiënten die met behandeling onder controle zijn of patiënten die ontvankelijk zijn voor aanvallen, mogen alleen met ZALDIAR of ZALDIAR BRUIS worden behandeld als dat absoluut noodzakelijk is. Gelijktijdig gebruik van opioïd-agonistenantagonisten (nalbufine, buprenorfine, pentazocine) wordt niet aangeraden. ZALDIAR en ZALDIAR BRUIS moeten met voorzichtigheid worden gebruikt bij opioïd-afhankelijke patiënten of bij patiënten met een craniaal trauma, met een aanleg voor convulsieve aandoeningen, galwegaandoeningen, in een toestand van shock, in een toestand van veranderd bewustzijn van onbekende oorzaak, met problemen van het ademhalingscentrum of de ademhalingsfunctie, of met een verhoogde intracraniale druk. Interacties: MAO-remmers, alcohol, carbamazepine en andere enzyminductoren, opioïd-agonisten-antagonisten, SSRI’s, triptanen, andere opioïdderivaten, benzodiazepinen, barbituraten, anxiolytica, hypnotica, sedatieve antidepressiva, sedatieve antihistaminica, neuroleptica, centraal werkende antihypertensieve middelen, thalidomide, baclofen, warfarines, andere geneesmiddelen waarvan bekend is dat ze CYP3A4 remmen, bupropion. Meest voorkomende bijwerkingen: misselijkheid, duizeligheid en slaperigheid, hoofdpijn, beven, verwardheid, stemmingswisselingen, slaapstoornissen, braken, constipatie, droge mond, diarree, abdominale pijn, dyspepsie, flatulentie, zweten, pruritus. Houdbaarheid: ZALDIAR 3 jaar / ZALDIAR BRUIS 2 jaar. Verpakking en prijs: ZALDIAR 30 of 60 tabletten per verpakking / ZALDIAR BRUIS 30 tabletten per verpakking. Prijs: zie Z-Index taxe. Registratienummer: ZALDIAR RVG 28113 / ZALDIAR BRUIS RVG 101592. Afleverstatus: UR. Vergoeding: volledig vergoed. Datering IB tekst: ZALDIAR Augustus 2010 en ZALDIAR BRUIS Maart 2010. Volledige productinformatie is op aanvraag verkrijgbaar: Grünenthal B.V., Kosterijland 70, 3981 AJ Bunnik. Tel: 030 – 60 463 70. E-mail: [email protected]. Website: www.grunenthal.nl

Ook als bruis beschikbaar

VERKORTE PRODUCTINFORMATIE QUTENZAHUIDPLEISTER

Farmacotherapeutische groep: Anti-epileptica, ATC code: N03AX16. Contra-indicaties: Overgevoeligheid voor het werkzame bestanddeel of voor één van de hulpstoffen. Waarschuwingen en voorzorgen: Diabetische patiënten die in gewicht toenemen tijdens de pregabalinebehandeling, kunnen een aanpassing van hun bloedsuikerverlagende geneesmiddelen nodig hebben. Er zijn post-marketing meldingen geweest van overgevoeligheidsreacties, inclusief gevallen van angio-oedeem. Pregabaline dient onmiddellijk te worden gestaakt indien zich symptomen van angio-oedeem voordoen, zoals zwellingen in het gezicht, rondom de mond of in de bovenste luchtwegen. Bij de behandeling met pregabaline zijn duizeligheid en slaperigheid opgetreden, wat het optreden van toevallige verwondingen (door vallen) bij oudere patiënten kan doen toenemen. Er zijn ook post-marketing meldingen geweest van verlies van bewustzijn, verwardheid en geestelijke achteruitgang. Daarom dient patiënten aangeraden te worden om voorzichtig te zijn tot ze vertrouwd zijn met de mogelijke effecten van het geneesmiddel. Bijwerkingen van het gezichtsvermogen: in gecontroleerde onderzoeken werd bij een groter gedeelte van de patiënten die met pregabaline werden behandeld in vergelijking met de patiënten die placebo kregen wazig zicht gemeld, dat in een meerderheid van de gevallen bij het voortzetten van de dosering vanzelf verdween. In klinische studies waarin oogheelkundige testen werden uitgevoerd, was de incidentie van verminderde gezichtsscherpte en veranderingen van het gezichtsveld groter in de patiëntengroep die met pregabaline werd behandeld dan in de placebogroep. De incidentie van fundoscopische veranderingen was groter in de placebogroep. Tijdens de postmarketingervaring zijn ook bijwerkingen van het gezichtsvermogen gemeld, inclusief verlies van het gezichtsvermogen, wazig zicht of andere veranderingen van de gezichtsscherpte, waarvan de meeste tijdelijk waren. Het staken van de behandeling met pregabaline kan resulteren in het verdwijnen of verbeteren van deze visuele symptomen. Gevallen van nierfalen zijn gemeld en in sommige gevallen vertoonde het stoppen met pregabaline reversibiliteit van deze bijwerking. Er zijn onvoldoende gegevens bekend met betrekking tot het stopzetten van antiepileptische co-medicatie na het bereiken van een controle van de aanvallen met pregabaline in de combinatietherapie, met als doel monotherapie met pregabaline te bereiken. Na stopzetting van korte- en langetermijnbehandelingen met pregabaline zijn onttrekkingsverschijnselen waargenomen bij sommige patiënten. De volgende voorvallen zijn gemeld: slapeloosheid, hoofdpijn, misselijkheid, angst, diarree, griepsyndroom, zenuwachtigheid, depressie, pijn, hyperhidrose en duizeligheid. De patiënt dient hiervan op de hoogte gebracht te worden bij het begin van de behandeling. Convulsies, inclusief status epilepticus en tonisch-clonische aanvallen, kunnen voorkomen tijdens het gebruik van pregabaline of kort na het stopzetten van de behandeling met pregabaline. Wat betreft de stopzetting van een langdurige behandeling met pregabaline zijn geen gegevens beschikbaar over de incidentie en ernst van de abstinentieverschijnselen in verhouding tot de gebruiksduur en de dosis van pregabaline. Er zijn post-marketing meldingen geweest van congestief hartfalen bij een aantal patiënten die pregabaline kregen. Pregabaline dient met voorzichtigheid te worden gebruikt bij oudere cardiovasculair gecompromitteerde patiënten. Tijdens de behandeling van centrale neuropathische pijn veroorzaakt door letsel van het ruggenmerg was de incidentie van bijwerkingen in het algemeen, CZS-gerelateerde bijwerkingen en in het bijzonder slaperigheid verhoogd. Dit kan toe te schrijven zijn aan het bijkomend effect van gelijktijdig toegediende geneesmiddelen (bijv. geneesmiddelen tegen spasticiteit) die nodig zijn voor deze aandoening. Dit dient overwogen te worden bij het voorschrijven van pregabaline bij deze aandoening. Het optreden van suïcidale ideevorming en - gedrag is gemeld bij patiënten die behandeld werden met anti-epileptica bij verschillende indicaties. Een meta-analyse van gerandomiseerde placebogecontroleerde onderzoeken met anti-epileptica laat ook een kleine toename van het risico zien op suïcidale ideevorming en gedrag. Het mechanisme achter dit risico is niet bekend en de beschikbare gegevens sluiten de mogelijkheid van een toegenomen risico voor pregabaline niet uit. Patiënten moeten daarom nauwkeurig gecontroleerd worden op tekenen van suïcidale ideevorming en gedrag en een geschikte behandeling dient te worden overwogen. Patiënten (en hun verzorgers) moeten erop gewezen worden dat indien er zich tekenen van suïcidale ideevorming of - gedrag voordoen er medisch advies ingewonnen moet worden. Er zijn post-marketing meldingen van voorvallen die verband houden met een verminderde werking van het onderste gedeelte van het maagdarmkanaal (bijv. darmobstructie, paralytische ileus, constipatie) wanneer pregabaline gelijktijdig werd toegediend met geneesmiddelen die constipatie kunnen veroorzaken zoals opioïde analgetica. Wanneer pregabaline en opioïden samen gebruikt worden, kunnen maatregelen overwogen worden om constipatie te voorkomen (vooral bij vrouwelijke patiënten en ouderen). Gevallen van misbruik zijn gemeld. Voorzichtigheid dient te worden betracht bij patiënten met een geschiedenis van drugsmisbruik. Deze patiënten dienen gecontroleerd te worden op symptomen van pregabalinemisbruik. Gevallen van encefalopathie zijn gemeld, voornamelijk bij patiënten met een onderliggende aandoening die het optreden van encefalopathie kan bespoedigen. Lyrica bevat lactosemonohydraat. Patiënten met zeldzame, erfelijke problemen van galactose-intolerantie, Lapp-lactase deficiëntie of glucosegalactose malabsorptie mogen dit geneesmiddel niet innemen. Interacties: Aangezien pregabaline voornamelijk onveranderd wordt uitgescheiden in de urine, nagenoeg niet wordt gemetaboliseerd bij de mens, in vitro het geneesmiddelenmetabolisme niet remt en niet aan plasma-eiwitten wordt gebonden, is het onwaarschijnlijk dat het farmacokinetische interacties teweeg zou brengen of er onderhevig aan zou zijn. Pregabaline kan de effecten van ethanol en lorazepam versterken. Tijdens post-marketing ervaring zijn er meldingen geweest van ademhalingsstilstand en coma bij patiënten die pregabaline en andere CSZ antidepressieve geneesmiddelen gebruikten. Pregabaline lijkt een additieve werking te hebben op de verstoring van de cognitieve en algemene motorische functie, veroorzaakt door oxycodone. Er zijn geen specifieke farmacodynamische interactiestudies uitgevoerd bij oudere vrijwilligers. Interactiestudies zijn alleen bij volwassenen uitgevoerd. Bijwerkingen: In het klinisch onderzoeksprogramma waren de bijwerkingen meestal mild tot matig in intensiteit. De opgesomde bijwerkingen kunnen ook verband houden met het onderliggende ziektebeeld en/of gelijktijdig toegediende geneesmiddelen. De meest voorkomende bijwerkingen die resulteerden in stopzetting van de pregabalinebehandeling waren duizeligheid en slaperigheid. Zeer vaak (≥ 1/10): duizeligheid en slaperigheid. Vaak (≥ 1/100, < 1/10): toegenomen eetlust, euforie, verwarring, geïrriteerdheid, afgenomen libido, desoriëntatie, slapeloosheid, ataxie, abnormale coördinatie, tremor, dysartrie, geheugenstoornis, concentratiestoornis, paresthesie, sedatie, evenwichtsstoornis, lethargie, wazig zien, diplopie, vertigo, braken, droge mond, constipatie, flatulentie, erectiele disfunctie, abnormale gang, een dronken gevoel hebben, vermoeidheid, perifeer oedeem, oedeem en gewichtstoename. Soms (≥ 1/1000, < 1/100): nasofaryngitis, anorexia, hypoglykemie, hallucinaties, paniekaanvallen, rusteloosheid, agitatie, depressie, terneergeslagenheid, stemmingsschommelingen, depersonalisatie, moeilijk op woorden kunnen komen, abnormale dromen, toegenomen libido, anorgasme, apathie, syncope, stupor, myoclonus, psychomotorische hyperactiviteit, ageusie, dyskinesie, posturale duizeligheid, intentie tremor, nystagmus, cognitieve functiestoornis, spraakstoornis, hyporeflexie, hypoesthesie, amnesie, hyperesthesie, brandend gevoel, abnormaal zien, oogzwellingen, gezichtsvelddefecten, verminderde gezichtsscherpte, oogpijn, asthenopie, droge ogen, verhoogde traanvorming, hyperacusis, tachycardie, eerste-graads atrioventriculair blok, blozen, warmteopwellingen, hypotensie, hypertensie, dyspnoe, droge neus, abdominale distensie, gastro-oesofagale refluxaandoening, toegenomen speekselproductie, orale hypoestesie, papuleuse huiduitslag, hyperhidrose, spiercontracties, zwelling van gewrichten, spierkramp, myalgie, artralgie, rugpijn, pijn in ledematen, spierstijfheid, urine incontinentie, dysurie, vertraagde ejaculatie, sexuele disfunctie, vallen, beklemd gevoel op de borst, asthenie, dorst, pijn, abnormaal gevoel, koude rillingen, verhoogd creatinine fosfokinase in het bloed, verhoogd alanine aminotransferase, verhoogd aspartaat aminotransferase en afname van het aantal bloedplaatjes. Zelden (< 1/1000): neutropenie, disinhibitie, toegenomen stemming, hypokinesie, parosmie, dysgrafie, perifeer gezichtsverlies, oscillopsie, afwijkende visuele diepteperceptie, fotopsie, oogirritatie, mydriasis, strabisme, visuele helderheid, sinus tachycardie, sinus bradycardie, sinus aritmie, perifere koudheid, epistaxis, toegeknepen keel, hoesten, verstopte neus, rhinitis, snurken, ascites, pancreatitis, dysfagie, urticaria, angstzweet, rhabdomyolyse, cervicale spasme, nekpijn, nierfalen, oligurie, amenorroe, galactorroe, borstpijn, dysmenorroe, borsthypertrofie, gegeneraliseerd oedeem, koorts, verhoogd glucose in het bloed, verlaagd kalium in het bloed, afname van het aantal witte bloedcellen, verhoogd creatinine in het bloed en gewichtsafname. Zeer zelden (< 1/10.000), frequentie niet bekend (gemeld vanuit post-marketing ervaring): overgevoeligheid, angio-oedeem, allergische reactie, agressie, verlies van bewustzijn, geestelijke achteruitgang, convulsies, hoofdpijn, malaise, verlies van het gezichtsvermogen, keratitis, congestief hartfalen, QT verlenging, pulmonair oedeem, gezwollen tong, diarree, misselijkheid, Stevens-Johnson-syndroom, jeuk, urineretentie en gezichtsoedeem. Afleveringsstatus: U.R. Registratienummers: EU/1/04/279/001-043. Vergoeding en prijzen: Lyrica wordt volledig vergoed binnen het GVS. Voor prijzen wordt verwezen naar de Z-Index taxe. Voor medische informatie over dit product belt u met 0800-MEDINFO (6334636). Zie ook www. lyrica.nl. De volledige productinformatie (SPC van augustus 2010) is op aanvraag verkrijgbaar. Registratiehouder: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, Verenigd Koninkrijk. Neem voor correspondentie en inlichtingen contact op met de lokale vertegenwoordiger: Pfizer bv, Postbus 37, 2900 AA Capelle a/d IJssel.

Postbus 37 2900 AA Capelle aan den IJssel www.pfizer.nl

EzPAP® Het nieuwe recruteren Verbeteren van de kwaliteit van leven

Patiënten met atelectase of long oedeem kunnen nu eenvoudig, effectief en comfortabel behandeld worden met de EzPAP®. De EzPAP® is een eenvoudig en geluidsarm systeem dat door middel van het COANDA effect de alveolen recruteerd.

EzPAP®

Wilt u meer weten? Bezoek onze website www.smiths-medical.nl

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Smiths Medical Belgium N.V. Excelsiorlaan 13 Bus 6, 1930 Zaventem T 02-704 49 00 F 02-720 44 34 [email protected]


31

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ingezonden

c o n tac t i n f o r m at i o n Department of Anesthesia Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305 USA

Conflict of interest P.J.A. van der Starre, MD, PhD H.J.H.M. Lemmens, MD, PhD

Met grote belangstelling hebben wij de Pro-Con discussie gelezen betreffende het gebruik van succinylcholine in het NTvA van november 2010 [1, 2]. Omdat sugammadex (nog steeds) niet is toegelaten door de FDA voor de Amerikaanse markt, is de conclusie van het Pro-argument van de auteurs Booij and Scheffer voor ons hier niet direct toepasbaar. In dezelfde uitgave staan verschillende advertenties gepubliceerd van MSD, na de overname

van Organon de huidige producent van sugammadex. We willen de redactie er op attenderen dat het tegenwoordig een algemeen geaccepteerde vereiste is dat auteurs bij hun publicaties in medische tijdschriften vermelden of er enig “conflict of interest” is. Met name wanneer de inhoud van het artikel het gebruik van commerciële produkten beschrijft, is het van groot belang dat de lezers van het tijdschrift ervan op de hoogte zijn in

hoeverre auteurs al dan niet financiële belangen bij de produkten hebben (gehad). Het is in dit kader opvallend dat in dezelfde uitgave in een artikel van van Vugt et al. [3] deze informatie wel wordt gegeven, hoewel er geen enkel commercieel product wordt besproken, waarvoor hulde. Wij willen de redactie aanraden om dit principe bij iedere publicatie aan te houden, zodat het beleid meer overeenstemt met internationale regels.

references 1. Booij L., Scheffer G. Succinylcholine should no longer be used in anesthesia and intensive care. Ned Tijdschr v Anesthesiologie 2010;22:9.

2. Schreiber J. Con: Succinylcholine should not be withdrawn from the anesthetic portfolio. Ned Tijdschr v Anesthesiologie 2010;22:10-11.

3. Van Vugt R., van Zanten A., Tjan D. Severe rhabdomyolysis after carbon monoxide poisoning. Ned Tijdschr v Anesthesiologie 2010;22:16-18.

note van de hoofdredacteur

Conflict of interest Naar aanleiding van deze inzending hebben wij het verzoek van de brief schrijvers voorgelegd aan de auteurs: Prof. Booij en Prof. Scheffer geven aan, dat zij onderzoek naar Bridion® doen en voordrachten hierover houden, maar geen enkel financieel belang in de Firma MSD hebben. J. Schreiber geeft aan, dat er geen conflict of interest voor zijn bijdrage bestaat. Zie ook het editorial! Dr. M. Klimek, hoofdredacteur

Het Nederlands Tijdschrift voor

Anesthesiologie kondigt met gepaste trots aan

prof. dr.

N

T

v

A

RITSEMA

VAN ECK

AWARD Van harte nodigen wij auteurs uit, werkzaam aan een Nederlandse afdeling Anesthesiologie, tot het indienen van hun internationale publicaties, die in de periode van 1 juli 2010 – 30 juni 2011 zijn gepubliceerd. Deze worden beoordeeld door een onafhankelijk expertcomité bestaande uit de Kernredacteuren NTvA en het Stichtingsbestuur NTvA. De drie meest oorspronkelijke publicaties worden beloond met geldprijzen bestaande uit:

1e award € 3.000,2e award € 2.000,3e award € 1.000,-

De winnende awards worden gepubliceerd in het NTvA met een explicatie van de hoofdredacteur, waarbij de winnende Awardauteur zich met het indienen van een publicatie verplicht tot een beschrijving van de inbedding van de publicatie en het onderzoek in een brede context. De uitreiking van de NTvA – Prof. Dr. Ritsema van Eck Awards vindt plaats tijdens de NVA – Wetenschapsdag 2011 met een feestelijk tintje.

Dien daarom zo spoedig mogelijk uw publicatie in Dit initiatief wordt mede mogelijk gemaakt door Graag voor 1 juli 2011 (artikelen met postdatum na 01.07.2011 kunnen niet in aanmerking komen voor de Awards) naar de redactie van het NTvA – [email protected] - onder vermelding NTvA – Prof. Dr. Ritsema van Eck Award 2011

Award voorwaarden zijn van toepassing; op te vragen bij de redactie van het NTvA via een e.mail: [email protected]

Changing tomorrow

Innovatie in pijn management Onder het motto ‘Changing tomorrow’ zet Astellas zich in om een aantal uitdagende medische aandoeningen op een fundamenteel andere, innovatieve wijze aan te pakken. Pijnbehandeling is één van deze speerpunten. De fysieke en emotionele uitdagingen die patiënten met pijn ervaren staan hierbij centraal. Astellas werkt vanuit die optiek in haar R&D programma aan alternatieve oplossingen om de pijn te bestrijden. Momenteel werkt Astellas aan nieuwe, effectieve behandelingen om het lichamelijk en geestelijk lijden van patiënten met pijn zo goed mogelijk te verlichten. Met een zo minimaal mogelijke belasting voor de patiënt. In de hoop en overtuiging de dag van morgen voor pijnpatiënten structureel te veranderen. www.astellas.nl

Nu kunt u snel en veilig antagoneren onafhankelijk van diepte

BRIDION® heft snel en veilig het neuromusculaire blok op, onafhankelijk van de diepte: Nu ook snelle opheffing van een diep blok – 2,7 minuten bij een rocuronium blok* – 3,3 minuten bij een vecuronium blok* Weinig kans op bijwerkingen Geen anticholinergica nodig

NIEUW 2008-NL-467

* Mediane waarde Verkorte productinformatie zie elders in dit blad

Uniek werkingsmechanisme: BRIDION inactiveert rocuronium en vecuronium door inkapseling.

Grip op spierverslapping

anesthesiologie Nederlands tijdschrift voor volume 23, juni 2011

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