Paul Nyquist

Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus

Objective: To investigate the feasibility, safety, and efficacy of a ketogenic diet (KD) for superrefractory status epilepticus (SRSE) in adults. Methods: We performed a prospective multicenter study of patients 18 to 80 years of age with SRSE treated with a KD treatment algorithm. The primary outcome measure was significant urine and serum ketone body production as a biomarker of feasibility. Secondary measures included resolution of SRSE, disposition at discharge, KD-related side effects, and long-term outcomes. Results: Twenty-four adults were screened for participation at 5 medical centers, and 15 were enrolled and treated with a classic KD via gastrostomy tube for SRSE. Median age was 47 years (interquartile range [IQR] 30 years), and 5 (33%) were male. Median number of antiseizure drugs used before KD was 8 (IQR 7), and median duration of SRSE before KD initiation was 10 days (IQR 7 days). KD treatment delays resulted from intravenous propofol use, ileus, and initial care received at a nonparticipating center. All patients achieved ketosis in a median of 2 days (IQR 1 day) on KD. Fourteen patients completed KD treatment, and SRSE resolved in 11 (79%; 73% of all patients enrolled). Side effects included metabolic acidosis, hyperlipidemia, constipation, hypoglycemia, hyponatremia, and weight loss. Five patients (33%) ultimately died. Conclusions: KD is feasible in adults with SRSE and may be safe and effective. Comparative safety and efficacy must be established with randomized placebo-controlled trials. Classification of evidence: This study provides Class IV evidence that in adults with SRSE, a KD is effective in inducing ketosis.

Novel Features of Tumors That Secrete Both Growth Hormone and Prolactin in Acromegaly

The most prominent previously reported clinical features of growth hormone (GH) and prolactin (PRL)-secreting pituitary adenomas associated with acromegaly have included the high incidence of galactorrhea in women and a generally more favorable response to dopamine agonist therapy. The authors analyzed a consecutive series of 62 acromegalic patients treated with transsphenoidal microsurgery. GH-PRL tumors were found in 30% of the patients. There was a significant difference in sex distribution between acromegalics with the GH-PRL tumor subtype and all other acromegalics. Women represented 73% of the GH-PRL immunostain subtype, as compared with the overall sex distribution of 33 women (53%) and 29 men (47%) for the entire series of acromegalic patients. Individuals with the GH-PRL subtype had significantly higher postoperative GH levels than those with the GH subtype, and significantly higher postoperative GH levels when compared with all other acromegalics with a variety of immunostain subtypes. Linear regression analysis of the pre- and postoperative GH data revealed that the increased postoperative GH levels in the GH-PRL immunostain subtype were independent of the invasiveness of the tumor and of sex of the subject. When the same linear regression technique was used, lower preoperative levels of thyroxine and thyroid-stimulating hormone were observed in the GH-PRL subtype. These data suggest inherent differences characteristic of tumors that secrete both growth hormone and prolactin.

Haptoglobin 2-2 Genotype Is Associated With Cerebral Salt Wasting Syndrome in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND Haptoglobin (Hp) genotype has been shown to be a predictor of clinical outcomes in subarachnoid hemorrhage. Cerebral salt wasting (CSW) has been suggested to precede the development of symptomatic vasospasm. OBJECTIVE To determine if Hp genotype was associated with CSW and subsequent vasospasm after aneurysmal subarachnoid hemorrhage. METHODS Hp genotypic determination was done for patients admitted with a diagnosis of subarachnoid hemorrhage. Outcome measures included CSW, delayed cerebral infarction, and Glasgow Outcome Score of 4 to 5 at 30 days. Criteria for CSW included hyponatremia <135 mEq/L, and urine output >4 L in 12 hours with urine sodium >40 mEq/L. RESULTS A total of 133 patients were included in the study. The 3 Hp subgroups did not differ in terms of baseline characteristics. CSW occurred in 1 patient (3.4%) with Hp 1-1, 8 (14.0%) patients with Hp 2-1, and 15 (31.9%) patients with Hp 2-2 (P = .004). In the multivariate regression model, Hp 2-2 was associated with CSW (odds ratio [OR]: 4.94; CI: 1.78-17.43; P = .01), but Hp 2-1 was not (OR: 2.92; CI: 0.56-4.95; P = .15) compared with Hp 1-1. There were no associations between Hp genotypes and functional outcome or delayed cerebral infarction. CSW was associated with delayed cerebral infarction (OR: 7.46; 95% CI: 2.54-21.9; P < .001). CONCLUSION Hp 2-2 genotype was an independent predictor of CSW after subarachnoid hemorrhage. Because CSW is strongly associated with delayed cerebral infarction, the use of Hp genotype testing requires more investigation, and larger prospective confirmation is warranted. Additionally, a more objective definition of CSW needs to be delineated.

Wet lungs and a battered brain stem: can we stop one if we cannot stop the other?

Critical Care Medicine www.ccmjournal.org 1373 The Cushing’s response and acute autonomic instability are often seen in the early stages of brain injury and are often caused by injuries of the diencephalon and brain stem. This response, in addition to signaling neurological injury, can result in end organ damage such as neurogenic pulmonary edema and stunned myocardium, which are associated with increased mortality in affected patients (1). Neurogenic pulmonary edema was first reported in 1918 and since has been studied extensively and is associated with many causes of neurological injury (2). The neurological structures associated with cardiopulmonary end organ damage lie within the brain stem. They include the hypothalamus and the medulla, areas A1 and A5 of the ventrolateral medulla, nuclei of the solitary tract, and the area postrema (3, 4). To date the pathophysiology of neurogenic pulmonary edema is attributed to the cathecholamine surge caused by damage to the brainstem. This surge causes increased activation of the αand β-adrenergic receptors in the venous beds in the pulmonary vasculature and the muscles of the myocardium (5). Experiments using alpha adrenergic blockers, as well as other pharmacological agents, have prevented neurogenic pulmonary edema and stunned myocardium in animal models of brain injury (1, 6). Truly effective abortive therapy has remained elusive in animal models. Agents reported effective in animals and humans include intrathecal lidocaine, chloropromazine, phentolamine infusion, or pretreatment with phenoxybenzamine (1, 6–8). In this issue of Critical Care Medicine, Lu et al (9) report the use of hexamethonium to reverse both the pulmonary and the cardiac effects of neurological injury caused by lesions in the nucleus tractus solitarus in a novel Sprague-Dawley rat model of the neurogenic pulmonary edema. The goal of this research was to develop strategies for potential therapy to treat the fulminant neurogenic cardiopulmonary complications of rhomboencephalitis. This is a common cause of death in patients infected with the Enterovirus 71, an endemic viral infection. To date no known agent has resulted in increased survival after the onset of cardiopulmonary collapse in this disease. The experiment incorporated a new animal model, which applied the microinjection of 6-hydroxydopamine into the nucleus tractus solitarus of Sprague-Dawley rats resulting in cardiopulmonary collapse. Cardiopulmonary changes were evaluated with and without postablation treatment with the autonomic nicotinic ganglionic blocker hexamethonium. Hexmethonium was infused 10 minutes after injection with 6-hydroxydopamine, at the begining of onset of systemic hypertension. Important events after injection of 6-hydroxydopamine were: neurogenic pulmonary edema, detected by increased secretion of “connexion 43” within 3 hours, severe hemorrhagic pulmonary edema, occurring within 6 hours of injection, and death within 7 hours. After the early infusion of hexamethonium at 10 minutes postinjection, there was immediate reversal of hypertension and eventual preservation of cardiac and pulmonary function resulting in survival of the treated animals. Hemorrhagic pulmonary edema and death at 6 to 7 hours were not observed after treatment. Hexamethonium is a nicotinic receptor antagonist that acts at the preganglionic nicotinic acetylcholine receptors Wet Lungs and a Battered Brain Stem: Can We Stop One If We Cannot Stop the Other?*

Ventriculostomy and Lytic Therapy for Intracerebral Hemorrhage

Intraventricular hemorrhage (IVH) frequently complicates intracranial hemorrhage (ICH) and is a significant independent contributor to morbidity and mortality, yet therapy directed at ameliorating intraventricular clotting has been limited and until recently, has not been subject to systematic evaluation. Thrombolytic therapy with placement of an external ventricular drain for management of severe IVH secondary to ICH has been investigated in multiple observational studies, small randomized controlled trials and several meta-analyses, soon to culminate with the completion of the 500 patient CLEAR IVH randomized controlled trial. We review conventional and lytic therapeutic approaches to severe IVH in the setting of small ICH, articulating the scope of the problem, management issues, and relevant questions for future research.

Toxicity with hyperoxia in brain injury? Retrospection identifies unforeseen obstacles.

Critical Care Medicine www.ccmjournal.org 469 11. Kirkpatrick AW, De Waele JJ, Ball CG et al: The secondary and recurrent abdominal compartment syndrome. Acta Clinica Belgica 2007; 62(Suppl 1); 60–65 12. Balogh Z, McKinley BA, Holcomb JB, et al: Both primary and secondary abdominal compartment syndrome can be predicted early and are harbingers of multiple organ failure. J Trauma 2003; 54:848–859

638: RISK OF ASAH INCREASES WITH TEMPERATURE DROPS AND COLDER TEMPERATURES EVEN IN HOT WHEATHER

Introduction: We have previously studied the relationship of aneurysmal subarachnoid hemorrhage (aSAH) incidence to seasonal and recent temperature changes in 1,168 incident aSAH observed over 2 decades. We found increasing relative risk of aSAH with colder temperatures and temperature drops primari

Intracerebral Hemorrhage: Future therapy in intracerebral hemorrhage and intraventricular hemorrhage: aspiration and thrombolysis

Vascular malformations constitute an important cause of intracranial hemorrhage especially in younger patients. These malformations may arise from any segment of the different functional units of the brain vasculature, including arteries, arterioles, capillaries, venules, and veins. Among vascular malformations causing intracranial hemorrhage, brain arteriovenous malformations (AVMs) are among the most frequently encountered. Brain AVMs commonly affect distal arterial branches and in roughly half of the cases, the malformation is found in the borderzone region shared by the distal anterior, middle, and/or posterior cerebral arteries. Cerebral angiography may help to differentiate brain AVMs from other types of intracranial anomalies with arterio-venous shunting. Resection of an associated developmental venous anomaly is contraindicated as its occlusion may lead to venous stasis, brain edema, and eventual hemorrhage. A developmental venous anomaly (DVA) is found in up to 30% of cerebral cavernous malformations (CCM) patients.

Critical Care Neurology

The subspecialty of neurologic critical care has come of age. In years past, neurosurgeons and some neurologists had to acquire a critical care skill set that permitted them to care for their patients in the neurosurgical postoperative care environment and in stroke centers. Intensive care physicians had only rudimentary knowledge of the neurologic physiology, anatomy, and pathology necessary to diagnose and effectively treat acute neurologic conditions. Over time, a few medical centers large enough to care for many neuroscience patients and also support the concept of subspecialty intensive care units (ICUs) have come to recognize the benefits of neurologic intensivists. Often serving as the epicenter of patient care, the neurologic ICU team assists in the management of patients with a diverse range of neurologic pathology and connects with other specialty areas in the neurosciences to provide the comprehensive care approach required. Now, the discipline is maturing. In this generation a substantial cadre of intensivists has finally emerged to support the needs of critically ill neurologic patients in this country. Welcome aboard!