ABSTRACT : After a brain injury, raised temperature may be due to a regulated readjustment in the hypothalamic ‘set-point’ in response to inflammation. The purpose of this report is to mention possible implications related to temperature and homeostasis of morphine treatment in a patient with brain injury. During the month previous to her hospitalization in our city she was treated for fever with paracetamol and metamizol without results. After 31 days with similar results, we changed to morphine IV considering the possibility of treating pain and fever. This option was successful and afterwards we changed to fentanyl patches, keeping fever absent. After 100 days of hospitalization, the patient was discharged to her home

ARRIAGA GARCIA RENDON, JULIO CESAR

Mendieta Zerón, Hugo

Lebanese Medical Journal

English

Repositorio Institucional de la Universidad Autónoma del Estado de México

Lebanese Medical Journal 2014 • Volume 62 (1) 57CAS CLINIQUE/ CASE REPORTREMISSION of CENTRAL FEVER with MORPHINE POST TRAUMATIC BRAIN INJURYhttp://www.lebanesemedicaljournal.org/articles/62-1/case3.pdfHugo MENDIETA ZERÓN1, Julio Cesar ARRIAGA GARCÍA RENDÓN2Mendieta Zerón H, Arriaga García Rendón JC. Remission ofcentral fever with morphine post traumatic brain injury. J MedLiban 2014 ; 62 (1) : 57-61.Mendieta Zerón H, Arriaga García Rendón JC. Rémission dela fièvre d’origine centrale par la morphine suite à une lésioncérébrale traumatique. J Med Liban 2014 ; 62 (1) : 57-61.ABSTRACT : After a brain injury, raised tempera-ture may be due to a regulated readjustment in thehypothalamic ‘set-point’ in response to inflamma-tion. The purpose of this report is to mention possi-ble implications related to temperature and homeo-stasis of morphine treatment in a patient with braininjury.During the month previous to her hospitalizationin our city she was treated for fever with paracetamoland metamizol without results. After 31 days withsimilar results, we changed to morphine IV consider-ing the possibility of treating pain and fever. Thisoption was successful and afterwards we changed tofentanyl patches, keeping fever absent. After 100 daysof hospitalization, the patient was discharged to herhome.Keywords : brain damage, central fever, morphineINTRODUCTIONSeveral areas of the hypothalamus, including the para-ventricular hypothalamus, the ventromedial hypothala-mus, the posterior hypothalamus and the dorsomedialhypothalamus have been implicated in thermogenesis. Ithas been also stated that maintenance of central tempera-ture is determined by the balance between heat productionand heat loss. Interesting studies on central drug effectsand its different responses related to temperature andhomeostasis have focused on opioids, which are known toinhibit the release of different neurotransmitters in thecentral nervous system and alter normal cerebral meta-bolism.Raised temperature may be due to a regulated readjust-ment in the hypothalamic ‘set-point’ in response to inflam-mation and infection, or it may occur as a consequence ofdamage to the hypothalamus and/or its pathways. Themitochondrial respiratory chain-linked oxidative phospho-rylation and calcium transport are compromised by trau-matic brain injury (TBI) and support the idea that oxidativestress and perturbation of cellular calcium homeostasisplay significant roles in TBI [1].Fever in patients with severe head injury is a common-ly-encountered diagnostic and management problem.Neurogenic fever is a noninfectious source of fever in thepatient with head injury and, if untreated, can cause dam-age to the brain in many ways. Until recently, neurogenicfever was thought to be a relatively rare consequence ofTBI, but other studies have reported that 4 to 37% of TBIsurvivors experience this sequela. Neurogenic fever isessentially a diagnosis of exclusion [2]. It is only whensepsis is excluded that neurogenic fever can be considered.Though brain temperature is indeed higher than the coretemperature in the acute phase of severe TBI, that signi-ficance is uncertain with regard to outcome prediction,since there has been a paucity of work on the use of directmethods of brain temperature monitoring [3].Hemodynamic data has shown that morphine increasesintracranial pressure and decreases mean arterial bloodpressure and cerebral perfusion pressure in patients withsevere brain injury. Also, several changes observed in ratsafter morphine microinjection into the anterior hypothala-mus showed a clear etiology of hypothermia as a centralresponse to morphine. The purpose of this report is tomention possible implications related to temperature andhomeostasis of morphine treatment in a patient with braininjury. 1Medical Research Center (CICMED), Autonomous Univer-sity of the State of Mexico (UAEMEx); Materno PerinatalHospital “Mónica Pretelini” (HMPMP), Toluca, México. 2The American British Cowdray Medical Center I.A.P., México.Correspondence: Hugo Mendieta Zerón, MD, PhD. e-mail: mezh_74@yahoo.comRÉSUMÉ : Après une lésion cérébrale, la tempéra-ture élevée peut être due à un réajustement régulépar l’hypothalamus en réponse à l’inflammation. Lebut de ce rapport est de mentionner les implicationspossibles liées à la température et à l’homéostase dutraitement morphinique chez une patiente ayant unelésion cérébrale. Au cours du mois précédant son hospitalisationdans notre ville, la fièvre avait été traitée avec paracé-tamol et métamisol, sans résultats. Après 31 jours derésultats similaires, nous avons opté pour la morphineIV envisageant la possibilité de traiter conjointementla douleur et la fièvre. Cette option a été un succès, etpar la suite nous avons utilisé les patchs de fentanylpour éliminer les accès de fièvre. La patiente a puregagner son domicile après cent jours d’hospitalisa-tion.Mots-clés : fièvre centrale, lésion cérébrale, morphineCASE REPORTA 23-year-old woman, who was victim of a car accident,was admitted to our institution on June 15, 2009. Due tothe TBI (Figure 1), she had undergone decompressivecraniectomy and subdural catheter placement for monitor-ing intracranial pressure. During one month she was treat-ed in an Intensive Care Unit with esomeprazole, ferroussulfate, metoclopramide, mannitol, sedation, relaxation,enteral diet based on alitraq, carbamazepine, tetrazepam,valproic acid, mechanical ventilatory support and finallygastrostomy. On the physical examination she arrived to our hospitalwith persistent fever, weighing 40 kg, with a 7 (4-1-2)Glasgow Coma Score (GCS), spontaneous eyelid open-ing, arreflectic right mydriasis, left eye with pupil diame-ter of 3 mm and papillary atrophy, meningeal signs wereabsent. She did not follow simple commands and after apainful stimulus she assumed decerebration position.There were no dysautonomias in addition to fever.Clinical dataElectroencephalogram (Figure 2) on two occasionsshowed severe brain damage with slow waves. To excludefever by infection, several studies were performed (axialcomputerized tomography of all the body, blood smear,chest X-ray, cerebrospinal fluid analysis, febrile reactions[Weil-Felix and Widal tests], hematic biometry, hemocul-ture, influenza A and B test, interleukin 1-ß, urine culture,etc.), all being normal. A tracheal aspiration culture waspositive for Pseudomona aeruginosa and was treatedagainst this pathogen until being negative. TreatmentHemotransfusions were realized as required whenevereuthermia occurred. Electrolyte disturbances were cor-rected and urinary flows closely watched. During themonth previous to her hospitalization in our city she wastreated for fever with paracetamol and metamizol withoutresults.After 31 days with similar clinical evolution, wechanged to morphine IV, 0.05 mg/kg/h, considering thepossibility of treating pain and fever. This option was suc-cessful with fever remission the following day (Figure 3).Afterwards, there was only one fever spike on day 33 withmorphine and from day 34 we observed an absolute re-mission that allowed us to switch to fentanyl patches,keeping fever absent. After 100 days of hospitalization,she was discharged to her home with a 7 (4-1-2) GCS.DISCUSSIONEven moderate temperature elevation soon after acutecerebral damage may markedly worsen initial brain in-jury. This effect may justify aggressive antipyretic treat-ment. An attempt to correct fever appears warranted in allpatients with acute cerebral damage in order to obtain abetter functional recovery and to limit maximally any fur-ther insult to the brain [4].In the brain, energy metabolism is mainly oxidative.The oxidative metabolism and heat production are, there-fore, strongly related. After major cerebral injuries, suchas subarachnoid haemorrhage or traumatic brain injury,cerebral temperature can often exceed systemic tempera-ture. Mitochondrial dysfunction is probably the cornerstone of these post-injury perturbations of brain tempera-ture. Understanding this phenomenon remains, however,not complete [5]. It is hoped that earlier diagnosis andappropriate intervention for central fever will lead toimproved outcomes [6].It has long been recognized that opioids such as mor-phine can produce a range of effects on body temperaturein a number of species including man [7-13], but only few58 Lebanese Medical Journal 2014 • Volume 62 (1)                          H. MENDIETA ZERÓN et al. – Central fever remission with morphineFIGURE 1. Magnetic resonance imaging showing sagittal (a) and axial (b) slices of the brain.abH. MENDIETA ZERÓN et al. – Central fever remission with morphine                          Lebanese Medical Journal 2014 • Volume 62 (1) 59studies have analyzed the impact of this drug in centralfever. Evidence has shown that hypothermia is certainlydue to a central action of morphine since it occurs whenmorphine is applied by microinjection into the anteriorhypothalamus. Within the last few years, a number ofstudies have been conducted to investigate whether mor-phine plays a role in temperature regulation, fever, andhypothermia [11,14]. Collected data has suggested that,according to the opioid/morphine receptor subtype that isstimulated, changes in temperature can be observed [12,15]. Mu agonists have been an important component ofpain treatment for thousands of years. The usual pharma-cokinetic parameters (half-life, clearance, volume of dis-tribution) of opioids have been known for some time.However, the metabolism has, until recently, been poor-ly understood, and there has been recent interest in therole of metabolites in modifying the pharmacodynamicresponse in patients, in both analgesia and adverse effects.A number of opioids are available for clinical use, includ-ing morphine, hydromorphone, levorphanol, oxycodone,and fentanyl [16].In experimental studies, morphine pharmacokinetics isdifferent in the brain compared with other tissues due tothe properties of the blood-brain barrier and the action ofefflux pumps. It has been reported in humans that thebasal state in which morphine is administered to patientsmay either obey an active efflux of morphine metabolismin a healthy brain tissue or on the other hand, follow anincrease in permeability in damaged parenchyma. A re-cent explanation for this statement is based on the P-glyco-protein membrane protein which transports substratesacross cerebral endothelial cells back to the blood streamand its permeability capacity to upstream morphine ab-sorption in focal mass lesions and brain swelling. Some studies have evaluated a down-regulation effect ofMu opioid receptors secondary to desensitization of Mu-Opioid-Receptor (MOR)-mediated G-protein activity dueto levels of tolerance and relation to central nervous systemmediated effects of morphine exposure. In an experimentalstudy, MOR blockade resulted in inhibition of adenylylcyclase activity and calcium channels and activation ofpotassium channels and several intracellular kinases. Thefinal observed effect was the production of hypothermia.Other authors have suggested that nitric oxide (NO) has anantipyretic function, and that several neuronal and periph-eral NO isoforms may interact with morphine doses, eitherto block or allow temperature changes.Neuroinflammation hypotheses also have proposedthat tendency of lowering central and peripheral bodytemperature after morphine administration can be linkedto an immune system response suppressing natural killercell activity, antibody responses, spleen and peripheralFIGURE 2.  Electroencephalogram showing severe cortical brain damage.FIGURE 3. Thermic curves from day 25 to 32 of hospitalization. Day 32 was the beginning of I.V. morphine infusion.(Thermic curves of more days are available if requested to the corresponding author.) H. MENDIETA ZERÓN et al. – Central fever remission with morphine                          Lebanese Medical Journal 2014 • Volume 62 (1) 61blood cell responses to mitogens and macrophage func-tion leading to a decrease of the inflammatory stimulimainly within the preoptic anterior hypothalamus.Available data indicate that ambient temperature, dose,specific opioid used and central or peripheral activity ofreceptors may greatly affect thermoregulatory responsesto opioids. Tolerance is one of the undesired potentialsecondary effects of morphine administration and it hasbeen suggested in experimental protocols that chronicexposure leads to a down-regulation of mu-opioid recep-tor mRNA in peripheral sensory ganglia supporting thisfact.Our patient had a chronic deficit in either sensing tem-perature elevations or activating heat dissipation mecha-nisms under thermal stress as was reported in anothercase [17].Evidence obtained in clinical and experimental studieshas demonstrated the importance and metabolic differ-ences observed on a healthy brain exposed to morphinecompared to a damaged tissue; this may lead to paradoxi-cal changes related to morphine pharmakocinetics andpotential intra- and extracranial effects. In rats, subcuta-neous injection of morphine produces either a fall or a risein body temperature according to dosage; future clinicalevidence based on ethical support may lead to concreteexplanation of this statement in humans.Strong evidence related to temperature changes aftermorphine administration in humans with brain injury islimited, but the distinct roles of Mu and K receptor typesmay be important in understanding the mechanisms ofopioid-induced effects on body temperature, and thesereceptors may also play specific roles in thermoregulation.As mentioned above, suggested links between the opioidand immune systems may lead to a better understandingof temperature regulation pathogenesis and fu-ture thera-peutic approaches. In summary, The pathophysiology and management ofneurogenic fever is not well understood and needs moreresearch and understanding for better management and afavorable outcome. We propose morphine as an anti-pyretic option in a context that justifies its other systemicand multiple effects as an advantage for patients withbrain injury or trauma with no response to hyperthermiastandardized treatment, and after excluding potential fevercauses. Possible adverse effects of this treatment includebehavioral and neuro-adaptive effects of morphine, likeneural plasticity, dependence, withdrawal and antinoci-ception, probably caused as a consequence of glutamater-gic influence. ACKNOWLEDGMENTSAuthors thank Céline Plisson for her excellent help withthe French correction of the abstract.CONFLICT OF INTEREST: None disclosed.REFERENCES1. Xiong Y, Peterson P L, Lee CP. Alterations in cerebralenergy metabolism induced by traumatic brain injury.Neurol Res 2001; 23: 129-38.2. Childers MK, Rupright J, Smith DW. Post-traumatichyperthermia in acute brain injury rehabilitation. BrainInj 1994; 8: 335-43.3. Agrawal A, Timothy J, Thapa A. 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Konecka AM, Sadowski B, Jaszczak J, Panocka I,Sroczynska I, Misicka A. The effect of intracerebroven-tricular infusion of morphine, methionine-enkephalinand D-Ala2-enkephalinamide on body temperature ofrabbits. Arch Int Physiol Biochim 1982; 90: 1-7.10. Fischer MO, Dequire PM, Kalem A, Gerard JL, Plaud B.[Hypothermia after spinal anaesthesia: implication ofmorphine?]. Ann Fr Anesth Reanim 2006; 25: 296-8.11. Koek W, France CP, Javors MA. Morphine-inducedmotor stimulation, motor incoordination, and hypother-mia in adolescent and adult mice. Psychopharmacology(Berl) 2012; 219: 1027-37.12. Baker AK, Meert TF. Functional effects of systemicallyadministered agonists and antagonists of mu, delta, andkappa opioid receptor subtypes on body temperature inmice. J Pharmacol Exp Ther 2002; 302: 1253-64.13. Ryan KF, Price JW, Warriner B, Choi PT. Persistenthypothermia after intrathecal morphine: case report andliterature review. Can J Anaesth 2012; 59: 384-8.14. Vezina P, Stewart J. Hyperthermia induced by morphineadministration to the VTA of the rat brain: an effect dis-sociable from morphine-induced reward and hyperactiv-ity. Life Sci 1985; 36: 1095-105.15. Clark WG. Influence of opioids on central thermoregula-tory mechanisms. Pharmacol Biochem Behav 1979; 10:609-13.16. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharma-cology. Pain Physician 2008; 11: S133-S153.17. Whyte J, Filion DT, Rose TR. Defective thermoregula-tion after traumatic brain injury. A single subject evalua-tion. Am J Phys Med Rehabil 1993; 72: 281-5.

Remission of central fever with morphine post traumatic brain injury

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Remission of central fever with morphine post traumatic brain injury

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