Introduction maintaining an adequate cerebral perfusion pressure and

Brain Research 881 2000 88–97 www.elsevier.com locate bres Interactive report Hypothermia as an adjunctive treatment for severe bacterial 1 meningitis a , a a b c Jose E. Irazuzta , Robert Pretzlaff , Mark Rowin , Kevin Milam , Frank P. Zemlan , a Basilia Zingarelli a Division of Critical Care , Children’s Hospital Medical Center, Cincinnati, OH, USA b Marshall University , Huntington, WV, USA c University of Cincinnati College of Medicine , Cincinnati, OH, USA Accepted 30 August 2000 Abstract Brain injury due to bacterial meningitis results in a high mortality rate and significant neurologic sequelae in survivors. The objective of this study was to determine if the application of moderate hypothermia shortly after the administration of antibiotics would attenuate the inflammatory response and increase in intracranial pressure that occurs in meningitis. For this study we used a rabbit model of severe Group B streptococcal meningitis. The first component of this study evaluated the effects of hypothermia on blood–brain barrier function and markers of inflammation in meningitic animals. The second part of the study evaluated the effects of hypothermia on intracranial pressure, cerebral perfusion pressure and brain edema. This study demonstrates that the use of hypothermia preserves CSF serum glucose ratio, decreases CSF protein and nitric oxide and attenuates myeloperoxidase activity in brain tissue. In the second part of this study we show a decrease in intracranial pressure, an improvement in cerebral perfusion pressure and a decrease in cerebral edema in hypothermic meningitic animals. We conclude that in the treatment of severe bacterial meningitis, the application of moderate hypothermia initiated shortly after antibiotic therapy improves short-term physiologic measures associated with brain injury.  2000 Elsevier Science B.V. All rights reserved. Theme : Disorders of the nervous system Topic : Infectious diseases Keywords : Meningitis; Hypothermia; Intracranial pressure; Cerebral perfusion pressure; Inflammation; Cleaved Tau protein

1. Introduction maintaining an adequate cerebral perfusion pressure and

avoiding hyperventilation [43,49]. This approach to the Current management of brain injury emphasizes the treatment of brain injury is developed largely from work maintenance of adequate physiologic substrate and attenua- on traumatic brain injury [48]. The study of the application tion of the inflammatory response in an attempt to prevent of these principles in other forms of brain injury i.e. secondary brain injury. This approach applies the princi- infectious is less well established. ples of improved cerebral perfusion and oxygen delivery in Providing adequate oxygen delivery and cerebral perfu- all patients with techniques to decrease oxygen consump- sion does not reverse the primary insult and the injured tion in the most severely affected [30]. Current recom- brain responds with a complex inflammatory cascade that mendations include lowering intracranial pressure ICP, is responsible for much of the secondary damage observed. The infiltration of neutrophils [6,17,60] the production of inflammatory mediators [9,36,44] and the liberation ex- citatory amino acids [12,59,29] are common findings in 1 Published on the World Wide Web on 13 Semptember 2000. brain injury. Additionally, meningitic brain injury results Corresponding author. Division of Critical Care, One Children’s in areas of ischemia and necrosis secondary to vasculitis Plaza, Dayton, OH 45404-1815, USA. Tel.: 11-937-463-5168; fax: and areas of cerebritis secondary to neutrophil infiltration 11-937-463-5082. E-mail address : irazuztaaol.com J.E. Irazuzta. [32,57]. 0006-8993 00 – see front matter  2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 8 9 4 - 8 J .E. Irazuzta et al. Brain Research 881 2000 88 –97 89 Cerebral edema with an increase in ICP and sudden Care and Use of Laboratory Animals published by the herniation is the often fatal outcome of bacterial meningitis National Institutes of Health National Academy Press — [26,31,46]. The raised ICP common to patients with revised 1996 and was performed with the approval of the meningitis often occurs within 12 h of admission to the Wright State University Laboratory Animal Care and Use hospital [27,46,47]. This time coincides with the increase Committee. Male white New Zealand rabbits 2.5–3 kg in the inflammatory response generated by antibiotic were housed under conventional conditions. All surgical therapy. This increase in the inflammatory response ex- procedures and the administration of bacteria were per- acerbates blood–brain barrier dysfunction and cerebral formed under anesthesia. Anesthesia consisted of an edema [53]. Recognizing the sequence of these events intramuscular administration of ketamine 30 mg kg and offers a window of opportunity for studying interventions xylazine 3 mg kg followed by a continuous administra- designed to attenuate the inflammatory response and treat tion of Isoflurane 1.5 and nitrous oxide 50. or prevent secondary brain injury. Group B Streptococcus — type III GBS were cultured To be successful interventions designed to attenuate the overnight in Todd–Hewitt broth and grown to logarithmic inflammatory response, brain edema and increased ICP phase. The morning of the experiment the bacteria were described in meningitis should modulate multiple points of washed and re-suspended in sterile saline. Meningitis was the cascade of events that leads to increased brain damage. induced by inoculation into the cisterna magna of the The neuroprotective role of hypothermia has been known animals with 0.4 ml of the GBS suspension after removal for some time and hypothermia has been demonstrated to of 0.4 ml of cerebrospinal fluid CSF. Sham animals have a beneficial effect at multiple points of brain injury received an inoculum containing sterile saline. progression [40,50]. Moderate hypothermia reduces cyto- kine production, nitric oxide generation, leukocyte infiltra- 2.2. Randomization tion and the release of excitatory amino acids [18,22,63]. A decrease in cerebral metabolism and preservation of energy Prior to randomization and sixteen hours after GBS stores has been documented, as well as, a decrease in inoculation the severity of meningitis was determined by cerebral edema [8,45,62]. In our laboratory we have two observers assigning a clinical severity score. Severity demonstrated that the application of moderate hypothermia of illness was scored as follows: 05Normal activity, 15 decreases excitatory amino acid release and neuronal stress Reduced ambulation, 25inability to stand for .5 s, 35 in meningitis [29]. Moderate hypothermia has also been evidence of paralysis, 45actively seizing for more than 5 utilized in traumatic brain injury to control increased min or comatose. Animals were paired by severity of intracranial pressure that has failed conventional therapy clinical symptoms and randomized to hypothermic 32– [55]. 348C or normothermic 37–398C conditions. Animals We postulate that the application of moderate hypo- were enrolled until there was a minimum of six survivors thermia shortly after the administration of the antibiotics in each treatment group. Four control Sham animals will attenuate the inflammatory response and increase in underwent the entire procedure but did not receive the ICP that occurs in meningitis. Instituting hypothermia bacterial inoculum and were handled as animals in the following antibiotic therapy has two characteristics that normothermic group. make its study appealing. Hypothermia following anti- biotic therapy simulates a realistic clinical situation. The 2.3. Induction of hypothermia second advantage is that because inflammation increases dramatically following antibiotic administration the use of Following randomization and instrumentation animals in hypothermia as a therapeutic intervention will be coordi- the hypothermic group were rendered hypothermic by nated with the time during which inflammation is in- covering their torso with a plastic bag containing ice. creased. This study was performed in two parts. The first Stable rectal temperature conditions hypothermic, 32– 1 ] was to evaluate the effects of moderate hypothermia on the 348C; normothermic, 37–398C were obtained within 1 h 2 integrity of the blood–brain barrier and inflammatory of initiating the antibiotic therapy. In a pilot study rectal markers of brain injury. The second was to evaluate the and brain temperatures were equivalent in this model data effects of hypothermia on intracranial pressure and the not shown. Instrumentation involved placement of a maintenance of an adequate cerebral perfusion pressure in tracheotomy, a rectal probe, as well as, arterial and venous animals with severe bacterial meningitis. catheters. Ventilatory support was initiated and titrated to maintain a pH of .7.28, a PaCO of between 30 and 40 2 Torr and a PaO .100 Torr. Following instrumentation 2 

2. Material and methods animals were given a 20 ml kg bolus of Hespan Excel ,