International Journal of Neuroscience, 2015; Early Online: 1–6 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.985294
ORIGINAL ARTICLE
Neuroprotection of nalmefene for postoperative patients with spontaneous intracerebral hemorrhage Jun Zheng,1 Hao Li,1 Rui Guo,1 Ruiqi Chen,1 Sen Lin,1 Ming Liu,2 and Chao You1
Int J Neurosci Downloaded from informahealthcare.com by University of Waterloo on 03/03/15. For personal use only.
1
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; 2 Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China Background: Endogenous opiates play an important role in the secondary injury of brain tissue after central nervous system injury. It was confirmed that nalmefene, an opiates receptor antagonist, has neuroprotective efficacy in animal models. However, evidence of nalmefene treatment for surgical patients with spontaneous intracerebral hemorrhage is insufficient. Methods: Outcomes of patients treated with nalmefene were retrospectively compared with that of patients without any anti-opiate treatment. The primary outcome was functional outcome at 6 months post ictus, which was assessed using modified Rankin Scales (mRSs). Secondary outcomes included mortality in 30 d post ictus, state of consciousness evaluated using Glasgow Coma Scale (GCS) at 1, 3, 7 d post operation and complications. Results: Of 79 patients in the nalmefene treatment group, 22 (27.85%) had a favorable functional outcome at 6 months, while in the control group, 12 of 72 (16.67%) had the same result (p = 0.273). A significantly better outcome was observed in the treatment group during only one subgroup analyses which was GCS between 3 and 8 (32.26% vs. 6.45%, p = 0.006). Conclusions: Nalmefene treatment was safe for patients with spontaneous intracerebral hemorrhage but could not improve the outcome of either short-term consciousness or long-term functional outcome. KEYWORDS: intracerebral hemorrhage, opiate receptor antagonist, neuroprotection
Introduction Spontaneous intracerebral hemorrhage (sICH) is the most devastative kind of stroke. The case fatality rate at 30 d of sICH is about 30%–55% and only 12%–39% of the survivors could live independently after 6 months [1–3]. After primary mechanical injury caused by sICH and peri-hematoma brain tissue ischemia, levels of many neurotransmitters were elevated. The neurotransmitters including excitory amino acids such as glutamate and endogenous opiates take part in the secondary injury of brain tissue [4,5]. It was confirmed that the action of glutamate on the N-methyl-D-aspartate (NMDA) receptor potentiates edema and cellular necrosis [4]. Endogenous opiates such as dynophin and β-endorphin (β-EP) secreted by pituitary were elevated in both Received 9 July 2014; revised 18 October 2014; accepted 3 November 2014. Jun Zheng, Hao Li, contributed equally to this work. Correspondence: Chao You, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Tel: +86-028-85422972; Fax: +86-028-85422490; E-mail: ns [email protected]
plasma and cerebrospinal fluid after brain tissue injury [6]. A lot of studies showed that elevated dynorphin might lead to secondary tissue injury through acting on the κ opioid receptor [7–9]. It was reported that the secondary tissue injury induced by dynorphin was related with excessive neuronal excitation, blood-brain barrier disruption and brain edema, whereas antibodies to dynorphin could attenuate these pathophysiology progress after central nervous system injury [10,11]. Some further studies showed that the naloxone, an opiate receptor antagonist, could limit the adverse physiopathologic, histologic and behavioral changes after local or global ischemia in animal model [12,13]. However, clinical trials showed that better outcome was not observed in patients with acute cerebrovascular disease who were treated with naloxone [14,15]. Nalmefene is another opiate antagonist structurally similar to naloxone. Compared with naloxone, nalmefene has a substantially longer half-life (8.6 h) and an about 28-fold higher biding affinity for κ opioid receptor [16]. Previous studies showed that nalmefene treatment could improve neurological recovery after traumatic spinal cord injury and brain injury in animal
1
Int J Neurosci Downloaded from informahealthcare.com by University of Waterloo on 03/03/15. For personal use only.
2
J. Zheng et al.
model, and the neuroprotective function of nalmefene might relate to improvement of cellular bioenergetics state after trauma [17,18]. Another two studies showed that nalmefene was also effective in cerebral ischemia and the mechanism might be improving metabolic recovery, limiting reperfusion injury and inhibiting glutamate release in rats [9,19]. It was confirmed that nalmefene is safe and well tolerated in human, but the efficacy on neurological recovery of nalmefene is controversial. Several studies showed that nalmefene was beneficial for the patients with brain injury after trauma or operation [20,21], while results of a phase III clinical study failed to find any treatment benefit of nalmefene in patients with acute ischemic stroke [22]. Of all the patients with sICH, quite a number need surgical treatment. The additional traumatization from surgery could accelerate secretion of endogenous opiates, which might potentiate secondary injury of brain tissue. Nalmefene, the opiate-receptor antagonist, has neuroprotective potential after surgery for patients with sICH in theory. Moreover, it was confirmed that nalmefene could antagonize respiratory depression induced by opioids after operation [23]. Though a lot of evidence showed that nalmefene is likely to be beneficial for patient with sICH, there is no clinical study on nalmefene treatment for patients with sICH. In order to provide evidence for clinical practice, here we present a pilot clinical study to investigate the efficacy of nalmefene treatment in postoperative patients with sICH.
Methods Patients This study was approved by the Biological and Medical Ethics Committee (BMEC) of West China Hospital. We retrospectively reviewed the medical records of the patients with spontaneous intracerebral hemorrhage from October 2012 to September 2013. Adult patients with sICH who met the indications of surgery and received surgical treatment were included. Patients were excluded if: hemorrhage caused by secondary factors (intracranial tumor, arteriovenous malformation or aneurysm); contraindications of nalmefene treatment existed; with history of ischemic stroke or hemorrhage was secondary to ischemic stroke; preexisting dementia or disability. Indications and contraindications are listed in the appendix.
Treatment After hospitalized into stroke unit, medical history and neurologic physical examination were recorded immediately. Routine laboratory examinations and CT scan
were performed at the same time. The laboratory examinations included blood routine examinations, biochemical examinations and coagulation studies. All the patients had their vital signs monitored and were given supportive treatments in time. Surgeries were conducted by a special sICH treatment group consisted of well-trained neurosurgeons. All the patients received standard medical treatments of sICH followed the recommendations of ASA/AHA guidelines and clinical experience after operation in stroke unit or neurological intensive care unit [24]. Other individual treatments were given based on the clinical condition of patients. Nalmefene treatment began in 6 h after operation and kept for 3 d. Nalmefene (0.2 mg) was given by intravenous infusion in 100 ml 0.9% normal saline daily.
Outcomes Patients were all followed up for at least 6 months. Primary outcomes were the functional outcome of survivals at 6 months post ictus. The neurological functional status was evaluated by using the modified Rankin Scale (mRS). Secondary outcomes included mortality in 30 d post ictus, state of consciousness evaluated by using GCS at 1, 3, 7 d post operation and complications. The complications included pulmonary infection, gastrointestinal bleeding, liver damage and acute renal injury. Liver damage was judged by elevated liver enzymes (ALT, alanine aminotransferase; AST, aspartate aminotransferase). Acute renal injury was defined as an elevation of blood creatinine more than 26.4 umol/L (or >50% than the baseline blood creatinine), or decreased urine output (
ORIGINAL ARTICLE
Neuroprotection of nalmefene for postoperative patients with spontaneous intracerebral hemorrhage Jun Zheng,1 Hao Li,1 Rui Guo,1 Ruiqi Chen,1 Sen Lin,1 Ming Liu,2 and Chao You1
Int J Neurosci Downloaded from informahealthcare.com by University of Waterloo on 03/03/15. For personal use only.
1
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; 2 Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China Background: Endogenous opiates play an important role in the secondary injury of brain tissue after central nervous system injury. It was confirmed that nalmefene, an opiates receptor antagonist, has neuroprotective efficacy in animal models. However, evidence of nalmefene treatment for surgical patients with spontaneous intracerebral hemorrhage is insufficient. Methods: Outcomes of patients treated with nalmefene were retrospectively compared with that of patients without any anti-opiate treatment. The primary outcome was functional outcome at 6 months post ictus, which was assessed using modified Rankin Scales (mRSs). Secondary outcomes included mortality in 30 d post ictus, state of consciousness evaluated using Glasgow Coma Scale (GCS) at 1, 3, 7 d post operation and complications. Results: Of 79 patients in the nalmefene treatment group, 22 (27.85%) had a favorable functional outcome at 6 months, while in the control group, 12 of 72 (16.67%) had the same result (p = 0.273). A significantly better outcome was observed in the treatment group during only one subgroup analyses which was GCS between 3 and 8 (32.26% vs. 6.45%, p = 0.006). Conclusions: Nalmefene treatment was safe for patients with spontaneous intracerebral hemorrhage but could not improve the outcome of either short-term consciousness or long-term functional outcome. KEYWORDS: intracerebral hemorrhage, opiate receptor antagonist, neuroprotection
Introduction Spontaneous intracerebral hemorrhage (sICH) is the most devastative kind of stroke. The case fatality rate at 30 d of sICH is about 30%–55% and only 12%–39% of the survivors could live independently after 6 months [1–3]. After primary mechanical injury caused by sICH and peri-hematoma brain tissue ischemia, levels of many neurotransmitters were elevated. The neurotransmitters including excitory amino acids such as glutamate and endogenous opiates take part in the secondary injury of brain tissue [4,5]. It was confirmed that the action of glutamate on the N-methyl-D-aspartate (NMDA) receptor potentiates edema and cellular necrosis [4]. Endogenous opiates such as dynophin and β-endorphin (β-EP) secreted by pituitary were elevated in both Received 9 July 2014; revised 18 October 2014; accepted 3 November 2014. Jun Zheng, Hao Li, contributed equally to this work. Correspondence: Chao You, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Tel: +86-028-85422972; Fax: +86-028-85422490; E-mail: ns [email protected]
plasma and cerebrospinal fluid after brain tissue injury [6]. A lot of studies showed that elevated dynorphin might lead to secondary tissue injury through acting on the κ opioid receptor [7–9]. It was reported that the secondary tissue injury induced by dynorphin was related with excessive neuronal excitation, blood-brain barrier disruption and brain edema, whereas antibodies to dynorphin could attenuate these pathophysiology progress after central nervous system injury [10,11]. Some further studies showed that the naloxone, an opiate receptor antagonist, could limit the adverse physiopathologic, histologic and behavioral changes after local or global ischemia in animal model [12,13]. However, clinical trials showed that better outcome was not observed in patients with acute cerebrovascular disease who were treated with naloxone [14,15]. Nalmefene is another opiate antagonist structurally similar to naloxone. Compared with naloxone, nalmefene has a substantially longer half-life (8.6 h) and an about 28-fold higher biding affinity for κ opioid receptor [16]. Previous studies showed that nalmefene treatment could improve neurological recovery after traumatic spinal cord injury and brain injury in animal
1
Int J Neurosci Downloaded from informahealthcare.com by University of Waterloo on 03/03/15. For personal use only.
2
J. Zheng et al.
model, and the neuroprotective function of nalmefene might relate to improvement of cellular bioenergetics state after trauma [17,18]. Another two studies showed that nalmefene was also effective in cerebral ischemia and the mechanism might be improving metabolic recovery, limiting reperfusion injury and inhibiting glutamate release in rats [9,19]. It was confirmed that nalmefene is safe and well tolerated in human, but the efficacy on neurological recovery of nalmefene is controversial. Several studies showed that nalmefene was beneficial for the patients with brain injury after trauma or operation [20,21], while results of a phase III clinical study failed to find any treatment benefit of nalmefene in patients with acute ischemic stroke [22]. Of all the patients with sICH, quite a number need surgical treatment. The additional traumatization from surgery could accelerate secretion of endogenous opiates, which might potentiate secondary injury of brain tissue. Nalmefene, the opiate-receptor antagonist, has neuroprotective potential after surgery for patients with sICH in theory. Moreover, it was confirmed that nalmefene could antagonize respiratory depression induced by opioids after operation [23]. Though a lot of evidence showed that nalmefene is likely to be beneficial for patient with sICH, there is no clinical study on nalmefene treatment for patients with sICH. In order to provide evidence for clinical practice, here we present a pilot clinical study to investigate the efficacy of nalmefene treatment in postoperative patients with sICH.
Methods Patients This study was approved by the Biological and Medical Ethics Committee (BMEC) of West China Hospital. We retrospectively reviewed the medical records of the patients with spontaneous intracerebral hemorrhage from October 2012 to September 2013. Adult patients with sICH who met the indications of surgery and received surgical treatment were included. Patients were excluded if: hemorrhage caused by secondary factors (intracranial tumor, arteriovenous malformation or aneurysm); contraindications of nalmefene treatment existed; with history of ischemic stroke or hemorrhage was secondary to ischemic stroke; preexisting dementia or disability. Indications and contraindications are listed in the appendix.
Treatment After hospitalized into stroke unit, medical history and neurologic physical examination were recorded immediately. Routine laboratory examinations and CT scan
were performed at the same time. The laboratory examinations included blood routine examinations, biochemical examinations and coagulation studies. All the patients had their vital signs monitored and were given supportive treatments in time. Surgeries were conducted by a special sICH treatment group consisted of well-trained neurosurgeons. All the patients received standard medical treatments of sICH followed the recommendations of ASA/AHA guidelines and clinical experience after operation in stroke unit or neurological intensive care unit [24]. Other individual treatments were given based on the clinical condition of patients. Nalmefene treatment began in 6 h after operation and kept for 3 d. Nalmefene (0.2 mg) was given by intravenous infusion in 100 ml 0.9% normal saline daily.
Outcomes Patients were all followed up for at least 6 months. Primary outcomes were the functional outcome of survivals at 6 months post ictus. The neurological functional status was evaluated by using the modified Rankin Scale (mRS). Secondary outcomes included mortality in 30 d post ictus, state of consciousness evaluated by using GCS at 1, 3, 7 d post operation and complications. The complications included pulmonary infection, gastrointestinal bleeding, liver damage and acute renal injury. Liver damage was judged by elevated liver enzymes (ALT, alanine aminotransferase; AST, aspartate aminotransferase). Acute renal injury was defined as an elevation of blood creatinine more than 26.4 umol/L (or >50% than the baseline blood creatinine), or decreased urine output (
