American Journal of Emergency Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage Imo P. Aisiku, MD, MBA a,⁎, Peng Roc Chen, MD b, Hanh Truong, MD c, Daniel R. Monsivais, MD b, Jonathan Edlow, MD d a
Harvard University/Brigham and Womens Hospital, Boston, MA University of Texas Health Science Center Houston, Houston, TX 2609 Wooded Canyon, Katy, TX d Harvard University/Beth Israel Deaconnes Hospital, Boston, MA b c
a r t i c l e
i n f o
Article history: Received 20 November 2015 Received in revised form 26 December 2015 Accepted 27 December 2015 Available online xxxx
a b s t r a c t Background: Aneurysmal subarachnoid hemorrhage (SAH) is the most devastating form of hemorrhagic stroke. Primary predictors of mortality are based on initial clinical presentation. Initial serum lactic acid levels have been shown to predict mortality and disease severity. Initial serum lactate may be an objective predictor or mortality. Methods: Retrospective review of aneurysmal SAH in a large academic center over a 42-month period. Data collected included demographics, clinical data, serum, and clinical outcomes data. Epidemiologic data were collected at baseline, and patients were followed up through their inpatient stay. We compared data in the group of patients who were deceased (group A) vs survivors (group B). Results: There were a total of 249 patients. Mortality was 21.5%. Mean age was the same for both groups: 57 years (group A) and 55 years (group B). Mean admission serum lactate level was 3.5 ± 2.5 (group A) and 2.2 ± 1.6 (group B; P b. 0001). The range was 0.01 to 14.7. Multivariable analysis controlling for Hunt and Hess grades showed lactic acid levels to be an independent predictor of mortality with a P value of .0018. Conclusions: In aneurysmal SAH, elevated serum lactate levels on admission may have a predictive role for mortality and represent a marker of disease severity. Currently, lactic acid levels are not ordered on all patients with SAH but perhaps should be part of the routine initial blood work and may serve as an additional prognostic marker. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Aneurysmal subarachnoid hemorrhage (SAH) accounts for a small percentage of strokes but contributes disproportionally to morbidity. Subarachnoid hemorrhage accounts for 2% to 7% of all strokes but accounts for 27% of stroke-related years of life lost [1–5]. Despite significant advances in patient management [6–9] as evidenced by a gradually decreasing case fatality rate of approximately 0.5% per year [10], the mortality from SAH remains high. Overall, SAH mortality is approximately 40% at 1 week, with 10% to 15% of deaths occurring prehospital and 25% within 24 hours of initial bleeding [4,10,11,12]. Multiple clinical scales are used to assess the extent of rupture and severity of SAH and clinical outcomes. The 2 most widely used scales are the Hunt and Hess [13] and the World Federation of Neurological
Surgeons (WFNS) [14], with the latter primarily used in the research community. Hunt and Hess and WFNS correlate with mortality; higher scores predict higher mortality. The WFNS has a better interobserver correlation but is still less used clinically [15]. A third imaging scale, the Fisher and modified Fisher scales [16,17], quantifies blood on computed tomography to predict the risk of symptomatic cerebral vasospasm, currently the most devastating complication of SAH. Subarachnoid hemorrhage severity is traditionally graded using the Hunt and Hess scale at presentation. The Hunt and Hess scale relies on clinical observations. More objective markers of disease severity may help stratify patients for clinical decision making and epidemiologic reporting and provide greater interobserver reliability. We propose serum lactate as a simple objective adjunct to initial evaluation of SAH patients that may help identify patients at increased risk for mortality. 2. Methods
⁎ Corresponding author at: Harvard University/Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115 E-mail addresses: [email protected] (I.P. Aisiku), [email protected] (P.R. Chen), [email protected] (H. Truong), [email protected] (D.R. Monsivais), [email protected] (J. Edlow).
2.1. Study overview This study is a retrospective review of all patients presenting to a large academic hospital from January 1, 2008, to June 30, 2011. All
http://dx.doi.org/10.1016/j.ajem.2015.12.079 0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
2
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Table 1 Baseline clinical characteristics of aneurysmal SAH patients Characteristic
N = 451
Sex (female) Age (y) Age distribution (y) Race White Black Hispanic Other APACHE II Range GCS GCS ≤ 8 Hunt and Hess scale 1 2 3 4 5 Modified Fisher scale 1 2 3 4 Admission MAP (mm Hg) Mortality 48-h mortality
59% 55 ± 11 23-97 52% 18% 17% 13% 14 ± 7 0-30 11 ± 5 30% 6% 35% 20% 19% 20% 14% 20% 41% 35% 98 ± 19 22% 11%
SAH patients were admitted to the intensive care unit (ICU) and were part of a prospective database that included epidemiologic, serum, and selected cerebrospinal fluid (CSF) biomarkers when available. The patients in this study represent the cohort of patients admitted with a diagnosis of aneurysmal SAH. Initial patient selection criteria included all patients with an age greater than 18 years who presented with an International Classification of Diseases diagnosis code for SAH, epidural hematoma, intracranial aneurysm, and subdural hematoma. All medical records were electronically maintained including nursing, pharmacy, and respiratory. The patient medical records were manually reviewed, and all patients without a diagnosis of SAH (i.e. subdural hematoma, epidural hematoma), a nonaneurysmal SAH from trauma, arterialvenous malformation, or isolated intracerebral hemorrhage with no aneurysm were excluded from the cohort. The study was designed as an epidemiologic database review focusing on admission characteristics of all patients with SAH and prespecified outcome measures. All patients were admitted to the neuroscience ICU. 2.2. Variable description Predictor variables included in the study were predefined into the following categories; demographics, Acute Physiologic Data (vital signs), serum hematology (complete blood count and prothrombin time/partial thromboplastin time) and chemistries (arterial blood gases, urinalysis, urine toxicology screen, and serum ETOH) on admission and peak and low values during ICU course, severity of illness scales (Glasgow Coma Scale [GCS], Acute Physiology and Chronic Health Evaluation [APACHE] II, Sequential Organ Failure Assessment [SOFA], Hunt and Hess, and Fisher), chronic health information, mechanical ventilation, therapeutic interventions (colloids, renal replacement therapy, seizure prophylaxis, deep vein thrombosis prophylaxis, transfusions), complications, and medications. Demographic data, serum hematology and chemistries, complications, and chronic health information were directly abstracted from the medical records. Race was reported as white, African American, Hispanic, and other. Admission serum data was defined as the initial laboratory data obtained within the first 12 hours of presentation to the emergency department or the ICU. Respiratory data were abstracted from respiratory records. Medications and therapeutic interventions were abstracted from pharmacy and nursing
records for accuracy. Severities of illness variables (SOFA and APACHE II) were manually calculated through medical record–extrapolated data. Hunt and Hess and GCS were routinely recorded as part of the institutional standard clinical care and were abstracted from the medical record. Modified Fisher scales were routinely recorded and abstracted from the medical record, and all missing modified Fisher scale data were retrospectively assessed by 2 physicians in the study group and adjudicated by a third through clinical review of radiographic images. The primary outcomes measured were inpatient mortality, ICU length of stay (LOS), and hospital LOS. Secondary outcome measures included discharge location, ICU complications (ventilator associated pneumonia, central line–associated blood stream infection, catheterrelated urinary tract infection, and development of renal replacement therapy), and in-hospital complications (eg, deep vein thrombosis, acute lung injury). 2.3. Statistical analysis We evaluated admission predictors of mortality, inpatient hospital LOS, and ICU LOS. Continuous variables were dichotomized based on clinical thresholds for abnormality. χ 2 Analysis was used to evaluate categorical variables, and the Student t test was used for continuous variables. Univariate analyses were used to test for associations between predictor and outcome variables. Variables with significant associations (P b .01) were considered candidates for multivariable analyses. Multivariable models were constructed using general linear model with logistic regression function, extended by generalized estimating equations to account for within-subject variation. Tests for interaction and collinearity were performed for the final variables used in the model. The relationship between serum lactate and mortality was assessed using a multivariable model. The final model included Hunt and Hess scale, admission serum glucose, admission cardiac troponin T, admission arterial pH, admission temp, and admission serum lactate. Significance level was set at a α ≤ .05. 3. Results There were 817 patients initially identified with diagnosis of SAH. Three hundred sixty-six (44.7%) patients were excluded. Most patients were excluded for trauma. Other exclusion criteria included intraventricular hemorrhage, intracerebral hemorrhage, and age. There were 451 patients included in the final cohort, of these 249 patients had initial serum lactic acid levels that were included in the final analysis. The baseline characteristics of the SAH cohort are presented in Table 1. Patients' with serum lactate drawn differed from patients without lactate drawn by markers of disease severity including GCS, APACHE II, mean arterial pressure (MAP), and Hunt and Hess (Tables 2 and 3). Lactate levels when compared with the Hunt and Hess scale showed stepwise increases in lactate as severity of Hunt and Hess score increased (Fig. 1). Fifty-nine percent of patients were female with a mean age of 55 ± 14 years. On admission, the mean GCS was 11 ± 5 overall, with a mean GCS of 5 and 13 in the deceased and survived groups, respectively. Sixty-nine percent of the patients presented with a Hunt and Hess grade 3 or higher. Hospital LOS and ICU LOS in univariate analysis was associated with admission temperature, arterial pH, white blood cells, GCS, APACHE II, SOFA, Hunt Table 2 Characteristics of patients with serum lactate vs no lactate
Age Sex (female) Mean arterial blood pressure (mm Hg) GCS APACHE II
Lactate (n = 249)
No lactate (n = 202)
P
55 ± 14 60% 100 ± 21
56 ± 13 57% 95 ± 16
.5073 .5457 .0190
10 ± 5 15 ± 7.3
12 ± 4 12 ± 7.2
.0003 .0029
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx Table 3 Neurologic severity of illness scales by presence of lactate drawn Lactate (n = 249) Modified Fishera 1 2 3 4 Hunt and Hessa 1 2 3 4 5
No lactate (n = 202)
6.7% (50%) 6.7% (25%) 44.4% (59%) 42.2% (65%)
8.3% (50%) 25% (75%) 38.9% (41%) 27.8% (35%)
4.3% (32%) 22.3% (43%) 23.7% (58%) 23.0% (68%) 26.7% (67%)
12.4% (68%) 33.3% (57%) 22.9% (58%) 14.3% (32%) 17.1% (33%)
3
Table 4 Univariate predictors of mortality in final model P
Predictor
Survive
Deceased
.0109
Hunt and Hess (%) 1 2 3 4 5 Admission temperature (°C) Cardiac troponin T (ng/L) Serum glucose (mg/dL) Admission serum lactate (mmol/L) Arterial pH
100 96.9 93.0 68.1 24.1 36.0 .09 140.7 2.2 7.42
0 3.1 7.0 31.9 75.9 36.5 .62 187.9 3.5 7.37
.0142
Data in parentheses represent the percentages of patient with lactate levels within severity of disease scales. a Initial percentages represent percent of patients in their respective lactate groups.
and Hess, and race. Hunt and Hess, GCS, APACHE II, and SOFA were associated with increased hospital and ICU LOS as independent predictors. Overall mortality was 21.5%, with half of those deaths occurring within the first 48 hours. Univariate predictors of mortality that were included in the final multivariate analysis included Hunt and Hess, admission temperature, cardiac troponin T, serum glucose, and serum lactate (Table 4). Mean serum admission lactate for all patients was 2.6 ± 1.95 mmol/L with a range of .01 to 14.7 mmol/L. The admission serum lactate level was 3.5 ± 2.5 mmol/L in the deceased group and 2.2 ± 1.6 mmol/L in the survival group, with a P value less than .0001 (Fig. 2). Multivariable analysis showed serum lactate levels to be an independent predictor of mortality with a P value of .0018. 4. Discussion The pathophysiology of SAH is complicated and can be viewed from different perspectives. The most important clinical issue is the development of transient global ischemia [18]. The rupture of the intracranial aneurysm leads to transmission of blood with arterial pressure into the subarachnoid space, creating SAH. This results in elevation of intracranial pressure and of variable duration, decrease in cerebral perfusion pressure, and transient global brain ischemia that, in turn, generates a cascade of secondary events. One consequence of SAH that has been reported is an elevated stress response, which includes the release of adrenocorticotropic hormone, cortisol, and catecholamines [18–20]. The benefit or harm of the elevated stress response is poorly understood, but markers of elevated stress response may potentially be measured in the serum and CSF. Several studies have demonstrated that worse outcomes are associated with higher cerebral lactate and higher cerebral lactate/pyruvate
P b.0001
.0002 b.0001 b.0001 b.0001 .003
ratios after SAH [21,22]. The pathophysiologic mechanism remains unclear as Hutchinson et al [22] Oddo et al [23] demonstrated that SAH patients had patterns of elevated interstitial lactate elevations in the setting of tissue hyperglycolosis. Most of existing literature has demonstrated metabolic crisis to varying degrees primarily identified by cerebral microdialysis [23,24]. Using cerebral microdialysis in both animal and human models, temporal relationships have been established as early as 15 minutes after hemorrhage [25,26]. Serum biomarkers have revolutionized the diagnosis and treatment of many disease processes, most notably sepsis [27,28]. In SAH, comparatively little literature has been published for serum (rather than CSF) biomarkers. Early literature reporting elevated serum levels of creatine kinase, creatine kinase-MB, lactate dehydrogenase, glutamicoxaloacetic transaminase, and glutamic-pyruvic transaminase as being predictive of worse outcome have been inconsistent [29,30]. More recently, admission serum glucose has been associated with poor outcome [31]. A recent meta-analysis by Kruyt et al [32] evaluated more than 3000 patients and identified admission hyperglycemia as a predictor of poor outcome. Cardiac troponin has also been reported as a marker of not only cardiac injury, but also acute lung injury and mortality [33–36]. To our knowledge, serum lactate has not been reported as a serum biomarker for SAH patients. Although cerebral microdalysis is a wellresearched tool and provides valuable information on tissue and CSF substrates, it is not universally available and requires invasive monitoring. Our data demonstrate a relationship between serum lactate and multiple markers of disease severity both SAH specific and general disease specific. Lactate levels reached as high as 14.7 in these patients suggesting significant systemic disease burden. Our data suggest that clinicians with a suspicion of greater disease severity ordered lactate levels as demonstrated by percentage of patients with lactate levels per Hunt and Hess grading scale (Table 3). Interestingly, the mean
Fig. 1. Mean admission serum lactate by Hunt and Hess grade.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
4
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Fig. 2. Mean admission serum lactate by mortality.
MAP was higher in the group that had lactate levels drawn, although neither group means were hypotensive and may not have been a significant driver for ordering lactate levels. Elevated serum lactate in a disease process that is limited to intracranial pathology underscores the systemic impact of high-grade SAH. As with other diseases, lactate levels are likely predictors of disease severity in patients with devastating neurologic diseases and should be collected. The first 24 hours is the most critical aspect of most critically ill patients. Serum lactate is readily and easily obtainable and may provide useful information on patient disease severity and mortality. Additional prospective data are needed to validate this finding and identify potential cutoff points for prognostication. The study is retrospective analysis of a prospective database and therefore has inherent limitations. Missing data on Hunt and Hess scales and Fisher scales as well as severity of injury scales were collected retrospectively. The location of the aneurysm on angiogram was not recorded. The sample size precludes a mortality assessment by aneurysm location, and we do not believe that serum lactate is a sensitiveenough indicator to identify mortality based on aneurysm location independent from severity of disease. A significant limitation of our study is that not all patients received lactate levels. We are unable to determine with a high degree of certainty why different physicians ordered lactate levels and others did not. However, we postulated that lactate levels were drawn on patients who presented with a higher degree of illness. Our conjecture is derived from an analysis of the groups who had lactate levels drawn vs the group who did not. Table 2 demonstrates that there were no differences in demographics between the 2 groups, whereas there is a significant difference in GCS, APACHE II, and mean arterial blood pressure, all validated measures of disease severity. We believe that the differences in the patients with lactate levels compared with those not drawn show a bias toward the more severe patients on presentation having lactate levels drawn. The general markers of disease severity noted in Table 2 and further substantiated in Table 3 support our presumption that lactate levels were preferentially drawn on the higher-acuity patients. Table 3 compares well-validated markers of neurologic injury specific to SAH, the modified Fisher scale and the Hunt and Hess scales, and the group with the worse modified Fisher and Hunt and Hess scales had lactate levels drawn. In addition, we do not have data on lactate levels as a function of time from the onset of SAH. Lactate levels have been shown to be a marker of disease severity in other disease states and are reasonable to believe that it may also be representative of disease severity in SAH patients as well. Thirty-one percent of patients who died did not have serum lactate levels drawn, and therefore, no information on 31% of these patients is known. However, the severity scales have been well-established markers of mortality and the correlation of lactate with these markers (Fig. 1) supports our findings.
5. Conclusion In aneurysmal SAH, elevated lactic acid levels on admission may have a predictive role. Currently, lactic acid levels are not ordered on all patients with SAH but perhaps should be part of the routine initial blood work and may serve as an additional prognostic marker. Prospective studies on the predictive ability of serum lactate on mortality are needed to validate these findings.
References [1] Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med 2006;354:387–96. [2] Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 1997;28:491–9. [3] Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25–146. [4] Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003;2:43–53. [5] Johnston SC, Colford Jr JM, Gress DR. Oral contraceptives and the risk of subarachnoid hemorrhage: a meta-analysis. Neurology 1998;51:411–8. [6] Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360:1267–74. [7] Ryttlefors M, Enblad P, Kerr RS, Molyneux AJ. International subarachnoid aneurysm trial of neurosurgical clipping versus endovascular coiling: subgroup analysis of 278 elderly patients. Stroke 2008;39:2720–6. [8] Kramer AH, Zygun DA. Declining mortality in neurocritical care patients: a cohort study in southern Alberta over eleven years. Can J Anaesth 2013;60:966–75. [9] Damian MS, Ben-Shlomo Y, Howard R, Bellotti T, Harrison D, Griggs K, et al. The effect of secular trends and specialist neurocritical care on mortality for patients with intracerebral haemorrhage, myasthenia gravis and Guillain-Barre syndrome admitted to critical care: an analysis of the Intensive Care National Audit & Research Centre (ICNARC) National United Kingdom Database. Intensive Care Med 2013;39: 1405–12. [10] Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997;28:660–4. [11] Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 1994;25: 1342–7. [12] Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med 2006;355: 928–39. [13] Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14–20. [14] Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, et al. A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 1988;51:1457. [15] Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ. Interobserver variability of grading scales for aneurysmal subarachnoid hemorrhage. Stroke 2011;42:1546–9. [16] Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6: 1–9.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx [17] Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly Jr ES, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified Fisher scale. Neurosurgery 2006;59:21–7 discussion 21-27. [18] Nyberg C, Karlsson T, Hillered L, Ronne EE. Metabolic pattern of the acute phase of subarachnoid hemorrhage in a novel porcine model: studies with cerebral microdialysis with high temporal resolution. PLoS One 2014;9:e99904. [19] Espiner EA, Leikis R, Ferch RD, MacFarlane MR, Bonkowski JA, Frampton CM, et al. The neuro-cardio-endocrine response to acute subarachnoid haemorrhage. Clin Endocrinol (Oxf) 2002;56:629–35. [20] Zetterling M, Engstrom BE, Hallberg L, Hillered L, Enblad P, Karlsson T, et al. Cortisol and adrenocorticotropic hormone dynamics in the acute phase of subarachnoid haemorrhage. Br J Neurosurg 2011;25:684–92. [21] Nagel A, Graetz D, Schink T, Frieler K, Sakowitz O, Vajkoczy P, et al. Relevance of intracranial hypertension for cerebral metabolism in aneurysmal subarachnoid hemorrhage. Clinical article. J Neurosurg 2009;111:94–101. [22] Hutchinson P, O'Phelan K, et al. International multidisciplinary consensus conference on multimodality monitoring: cerebral metabolism. Neurocrit Care 2014; 21(Suppl 2):S148–58. http://dx.doi.org/10.1007/s12028-014-0035-3. [23] Oddo M, Levine JM, Frangos S, Maloney-Wilensky E, Carrera E, Daniel RT, et al. Brain lactate metabolism in humans with subarachnoid hemorrhage. Stroke 2012;43: 1418–21. [24] Helbok R, Ko SB, Schmidt JM, Kurtz P, Fernandez L, Choi HA, et al. Global cerebral edema and brain metabolism after subarachnoid hemorrhage. Stroke 2011;42: 1534–9. [25] Gewirtz RJ, Dhillon HS, Goes SE, DeAtley SM, Scheff SW. Lactate and free fatty acids after subarachnoid hemorrhage. Brain Res 1999;840:84–91. [26] Barcelos GK, Tholance Y, Grousson S, Renaud B, Perret-Liaudet A, Dailler F, et al. Outcome of poor-grade subarachnoid hemorrhage as determined by biomarkers of glucose cerebral metabolism. Neurocrit Care 2013;18:234–44.
5
[27] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637. [28] Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign Database. Crit Care Med 2015;43:567–73. [29] Maiuri F, Benvenuti D, Carrieri P, Orefice G, Carbone M, Carandente M. Serum and cerebrospinal fluid enzymes in subarachnoid haemorrhage. Neurol Res 1989;11:6–8. [30] Ruzak-Skocir B, Trbojevic-Cepe M. Study of serum and cerebrospinal fluid enzymes in diagnosis and differential diagnosis of cerebrovascular diseases. Neurologija 1990; 39:239–50. [31] Schlenk F, Vajkoczy P, Sarrafzadeh A. Inpatient hyperglycemia following aneurysmal subarachnoid hemorrhage: relation to cerebral metabolism and outcome. Neurocrit Care 2009;11:56–63. [32] Kruyt ND, Biessels GJ, de Haan RJ, Vermeulen M, Rinkel GJ, Coert B, et al. Hyperglycemia and clinical outcome in aneurysmal subarachnoid hemorrhage: a metaanalysis. Stroke 2009;40:e424–30. [33] Ahmadian A, Mizzi A, Banasiak M, Downes K, Camporesi EM, Thompson Sullebarger J, et al. Cardiac manifestations of subarachnoid hemorrhage. Heart Lung Vessels 2013;5:168–78. [34] Wybraniec MT, Mizia-Stec K, Krzych L. Neurocardiogenic injury in subarachnoid hemorrhage: a wide spectrum of catecholamin-mediated brain-heart interactions. Cardiol J 2014;21:220–8. [35] Chou SH, Robertson CS, Participants in the International Multi-disciplinary Consensus Conference on the Multimodality Monitoring. Monitoring biomarkers of cellular injury and death in acute brain injury. Neurocrit Care 2014. [36] Saritemur M, Akoz A, Kalkan K, Emet M. Intracranial hemorrhage with electrocardiographic abnormalities and troponin elevation. Am J Emerg Med 2013; 31(271):e275–7.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage Imo P. Aisiku, MD, MBA a,⁎, Peng Roc Chen, MD b, Hanh Truong, MD c, Daniel R. Monsivais, MD b, Jonathan Edlow, MD d a
Harvard University/Brigham and Womens Hospital, Boston, MA University of Texas Health Science Center Houston, Houston, TX 2609 Wooded Canyon, Katy, TX d Harvard University/Beth Israel Deaconnes Hospital, Boston, MA b c
a r t i c l e
i n f o
Article history: Received 20 November 2015 Received in revised form 26 December 2015 Accepted 27 December 2015 Available online xxxx
a b s t r a c t Background: Aneurysmal subarachnoid hemorrhage (SAH) is the most devastating form of hemorrhagic stroke. Primary predictors of mortality are based on initial clinical presentation. Initial serum lactic acid levels have been shown to predict mortality and disease severity. Initial serum lactate may be an objective predictor or mortality. Methods: Retrospective review of aneurysmal SAH in a large academic center over a 42-month period. Data collected included demographics, clinical data, serum, and clinical outcomes data. Epidemiologic data were collected at baseline, and patients were followed up through their inpatient stay. We compared data in the group of patients who were deceased (group A) vs survivors (group B). Results: There were a total of 249 patients. Mortality was 21.5%. Mean age was the same for both groups: 57 years (group A) and 55 years (group B). Mean admission serum lactate level was 3.5 ± 2.5 (group A) and 2.2 ± 1.6 (group B; P b. 0001). The range was 0.01 to 14.7. Multivariable analysis controlling for Hunt and Hess grades showed lactic acid levels to be an independent predictor of mortality with a P value of .0018. Conclusions: In aneurysmal SAH, elevated serum lactate levels on admission may have a predictive role for mortality and represent a marker of disease severity. Currently, lactic acid levels are not ordered on all patients with SAH but perhaps should be part of the routine initial blood work and may serve as an additional prognostic marker. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Aneurysmal subarachnoid hemorrhage (SAH) accounts for a small percentage of strokes but contributes disproportionally to morbidity. Subarachnoid hemorrhage accounts for 2% to 7% of all strokes but accounts for 27% of stroke-related years of life lost [1–5]. Despite significant advances in patient management [6–9] as evidenced by a gradually decreasing case fatality rate of approximately 0.5% per year [10], the mortality from SAH remains high. Overall, SAH mortality is approximately 40% at 1 week, with 10% to 15% of deaths occurring prehospital and 25% within 24 hours of initial bleeding [4,10,11,12]. Multiple clinical scales are used to assess the extent of rupture and severity of SAH and clinical outcomes. The 2 most widely used scales are the Hunt and Hess [13] and the World Federation of Neurological
Surgeons (WFNS) [14], with the latter primarily used in the research community. Hunt and Hess and WFNS correlate with mortality; higher scores predict higher mortality. The WFNS has a better interobserver correlation but is still less used clinically [15]. A third imaging scale, the Fisher and modified Fisher scales [16,17], quantifies blood on computed tomography to predict the risk of symptomatic cerebral vasospasm, currently the most devastating complication of SAH. Subarachnoid hemorrhage severity is traditionally graded using the Hunt and Hess scale at presentation. The Hunt and Hess scale relies on clinical observations. More objective markers of disease severity may help stratify patients for clinical decision making and epidemiologic reporting and provide greater interobserver reliability. We propose serum lactate as a simple objective adjunct to initial evaluation of SAH patients that may help identify patients at increased risk for mortality. 2. Methods
⁎ Corresponding author at: Harvard University/Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115 E-mail addresses: [email protected] (I.P. Aisiku), [email protected] (P.R. Chen), [email protected] (H. Truong), [email protected] (D.R. Monsivais), [email protected] (J. Edlow).
2.1. Study overview This study is a retrospective review of all patients presenting to a large academic hospital from January 1, 2008, to June 30, 2011. All
http://dx.doi.org/10.1016/j.ajem.2015.12.079 0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
2
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Table 1 Baseline clinical characteristics of aneurysmal SAH patients Characteristic
N = 451
Sex (female) Age (y) Age distribution (y) Race White Black Hispanic Other APACHE II Range GCS GCS ≤ 8 Hunt and Hess scale 1 2 3 4 5 Modified Fisher scale 1 2 3 4 Admission MAP (mm Hg) Mortality 48-h mortality
59% 55 ± 11 23-97 52% 18% 17% 13% 14 ± 7 0-30 11 ± 5 30% 6% 35% 20% 19% 20% 14% 20% 41% 35% 98 ± 19 22% 11%
SAH patients were admitted to the intensive care unit (ICU) and were part of a prospective database that included epidemiologic, serum, and selected cerebrospinal fluid (CSF) biomarkers when available. The patients in this study represent the cohort of patients admitted with a diagnosis of aneurysmal SAH. Initial patient selection criteria included all patients with an age greater than 18 years who presented with an International Classification of Diseases diagnosis code for SAH, epidural hematoma, intracranial aneurysm, and subdural hematoma. All medical records were electronically maintained including nursing, pharmacy, and respiratory. The patient medical records were manually reviewed, and all patients without a diagnosis of SAH (i.e. subdural hematoma, epidural hematoma), a nonaneurysmal SAH from trauma, arterialvenous malformation, or isolated intracerebral hemorrhage with no aneurysm were excluded from the cohort. The study was designed as an epidemiologic database review focusing on admission characteristics of all patients with SAH and prespecified outcome measures. All patients were admitted to the neuroscience ICU. 2.2. Variable description Predictor variables included in the study were predefined into the following categories; demographics, Acute Physiologic Data (vital signs), serum hematology (complete blood count and prothrombin time/partial thromboplastin time) and chemistries (arterial blood gases, urinalysis, urine toxicology screen, and serum ETOH) on admission and peak and low values during ICU course, severity of illness scales (Glasgow Coma Scale [GCS], Acute Physiology and Chronic Health Evaluation [APACHE] II, Sequential Organ Failure Assessment [SOFA], Hunt and Hess, and Fisher), chronic health information, mechanical ventilation, therapeutic interventions (colloids, renal replacement therapy, seizure prophylaxis, deep vein thrombosis prophylaxis, transfusions), complications, and medications. Demographic data, serum hematology and chemistries, complications, and chronic health information were directly abstracted from the medical records. Race was reported as white, African American, Hispanic, and other. Admission serum data was defined as the initial laboratory data obtained within the first 12 hours of presentation to the emergency department or the ICU. Respiratory data were abstracted from respiratory records. Medications and therapeutic interventions were abstracted from pharmacy and nursing
records for accuracy. Severities of illness variables (SOFA and APACHE II) were manually calculated through medical record–extrapolated data. Hunt and Hess and GCS were routinely recorded as part of the institutional standard clinical care and were abstracted from the medical record. Modified Fisher scales were routinely recorded and abstracted from the medical record, and all missing modified Fisher scale data were retrospectively assessed by 2 physicians in the study group and adjudicated by a third through clinical review of radiographic images. The primary outcomes measured were inpatient mortality, ICU length of stay (LOS), and hospital LOS. Secondary outcome measures included discharge location, ICU complications (ventilator associated pneumonia, central line–associated blood stream infection, catheterrelated urinary tract infection, and development of renal replacement therapy), and in-hospital complications (eg, deep vein thrombosis, acute lung injury). 2.3. Statistical analysis We evaluated admission predictors of mortality, inpatient hospital LOS, and ICU LOS. Continuous variables were dichotomized based on clinical thresholds for abnormality. χ 2 Analysis was used to evaluate categorical variables, and the Student t test was used for continuous variables. Univariate analyses were used to test for associations between predictor and outcome variables. Variables with significant associations (P b .01) were considered candidates for multivariable analyses. Multivariable models were constructed using general linear model with logistic regression function, extended by generalized estimating equations to account for within-subject variation. Tests for interaction and collinearity were performed for the final variables used in the model. The relationship between serum lactate and mortality was assessed using a multivariable model. The final model included Hunt and Hess scale, admission serum glucose, admission cardiac troponin T, admission arterial pH, admission temp, and admission serum lactate. Significance level was set at a α ≤ .05. 3. Results There were 817 patients initially identified with diagnosis of SAH. Three hundred sixty-six (44.7%) patients were excluded. Most patients were excluded for trauma. Other exclusion criteria included intraventricular hemorrhage, intracerebral hemorrhage, and age. There were 451 patients included in the final cohort, of these 249 patients had initial serum lactic acid levels that were included in the final analysis. The baseline characteristics of the SAH cohort are presented in Table 1. Patients' with serum lactate drawn differed from patients without lactate drawn by markers of disease severity including GCS, APACHE II, mean arterial pressure (MAP), and Hunt and Hess (Tables 2 and 3). Lactate levels when compared with the Hunt and Hess scale showed stepwise increases in lactate as severity of Hunt and Hess score increased (Fig. 1). Fifty-nine percent of patients were female with a mean age of 55 ± 14 years. On admission, the mean GCS was 11 ± 5 overall, with a mean GCS of 5 and 13 in the deceased and survived groups, respectively. Sixty-nine percent of the patients presented with a Hunt and Hess grade 3 or higher. Hospital LOS and ICU LOS in univariate analysis was associated with admission temperature, arterial pH, white blood cells, GCS, APACHE II, SOFA, Hunt Table 2 Characteristics of patients with serum lactate vs no lactate
Age Sex (female) Mean arterial blood pressure (mm Hg) GCS APACHE II
Lactate (n = 249)
No lactate (n = 202)
P
55 ± 14 60% 100 ± 21
56 ± 13 57% 95 ± 16
.5073 .5457 .0190
10 ± 5 15 ± 7.3
12 ± 4 12 ± 7.2
.0003 .0029
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx Table 3 Neurologic severity of illness scales by presence of lactate drawn Lactate (n = 249) Modified Fishera 1 2 3 4 Hunt and Hessa 1 2 3 4 5
No lactate (n = 202)
6.7% (50%) 6.7% (25%) 44.4% (59%) 42.2% (65%)
8.3% (50%) 25% (75%) 38.9% (41%) 27.8% (35%)
4.3% (32%) 22.3% (43%) 23.7% (58%) 23.0% (68%) 26.7% (67%)
12.4% (68%) 33.3% (57%) 22.9% (58%) 14.3% (32%) 17.1% (33%)
3
Table 4 Univariate predictors of mortality in final model P
Predictor
Survive
Deceased
.0109
Hunt and Hess (%) 1 2 3 4 5 Admission temperature (°C) Cardiac troponin T (ng/L) Serum glucose (mg/dL) Admission serum lactate (mmol/L) Arterial pH
100 96.9 93.0 68.1 24.1 36.0 .09 140.7 2.2 7.42
0 3.1 7.0 31.9 75.9 36.5 .62 187.9 3.5 7.37
.0142
Data in parentheses represent the percentages of patient with lactate levels within severity of disease scales. a Initial percentages represent percent of patients in their respective lactate groups.
and Hess, and race. Hunt and Hess, GCS, APACHE II, and SOFA were associated with increased hospital and ICU LOS as independent predictors. Overall mortality was 21.5%, with half of those deaths occurring within the first 48 hours. Univariate predictors of mortality that were included in the final multivariate analysis included Hunt and Hess, admission temperature, cardiac troponin T, serum glucose, and serum lactate (Table 4). Mean serum admission lactate for all patients was 2.6 ± 1.95 mmol/L with a range of .01 to 14.7 mmol/L. The admission serum lactate level was 3.5 ± 2.5 mmol/L in the deceased group and 2.2 ± 1.6 mmol/L in the survival group, with a P value less than .0001 (Fig. 2). Multivariable analysis showed serum lactate levels to be an independent predictor of mortality with a P value of .0018. 4. Discussion The pathophysiology of SAH is complicated and can be viewed from different perspectives. The most important clinical issue is the development of transient global ischemia [18]. The rupture of the intracranial aneurysm leads to transmission of blood with arterial pressure into the subarachnoid space, creating SAH. This results in elevation of intracranial pressure and of variable duration, decrease in cerebral perfusion pressure, and transient global brain ischemia that, in turn, generates a cascade of secondary events. One consequence of SAH that has been reported is an elevated stress response, which includes the release of adrenocorticotropic hormone, cortisol, and catecholamines [18–20]. The benefit or harm of the elevated stress response is poorly understood, but markers of elevated stress response may potentially be measured in the serum and CSF. Several studies have demonstrated that worse outcomes are associated with higher cerebral lactate and higher cerebral lactate/pyruvate
P b.0001
.0002 b.0001 b.0001 b.0001 .003
ratios after SAH [21,22]. The pathophysiologic mechanism remains unclear as Hutchinson et al [22] Oddo et al [23] demonstrated that SAH patients had patterns of elevated interstitial lactate elevations in the setting of tissue hyperglycolosis. Most of existing literature has demonstrated metabolic crisis to varying degrees primarily identified by cerebral microdialysis [23,24]. Using cerebral microdialysis in both animal and human models, temporal relationships have been established as early as 15 minutes after hemorrhage [25,26]. Serum biomarkers have revolutionized the diagnosis and treatment of many disease processes, most notably sepsis [27,28]. In SAH, comparatively little literature has been published for serum (rather than CSF) biomarkers. Early literature reporting elevated serum levels of creatine kinase, creatine kinase-MB, lactate dehydrogenase, glutamicoxaloacetic transaminase, and glutamic-pyruvic transaminase as being predictive of worse outcome have been inconsistent [29,30]. More recently, admission serum glucose has been associated with poor outcome [31]. A recent meta-analysis by Kruyt et al [32] evaluated more than 3000 patients and identified admission hyperglycemia as a predictor of poor outcome. Cardiac troponin has also been reported as a marker of not only cardiac injury, but also acute lung injury and mortality [33–36]. To our knowledge, serum lactate has not been reported as a serum biomarker for SAH patients. Although cerebral microdalysis is a wellresearched tool and provides valuable information on tissue and CSF substrates, it is not universally available and requires invasive monitoring. Our data demonstrate a relationship between serum lactate and multiple markers of disease severity both SAH specific and general disease specific. Lactate levels reached as high as 14.7 in these patients suggesting significant systemic disease burden. Our data suggest that clinicians with a suspicion of greater disease severity ordered lactate levels as demonstrated by percentage of patients with lactate levels per Hunt and Hess grading scale (Table 3). Interestingly, the mean
Fig. 1. Mean admission serum lactate by Hunt and Hess grade.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
4
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Fig. 2. Mean admission serum lactate by mortality.
MAP was higher in the group that had lactate levels drawn, although neither group means were hypotensive and may not have been a significant driver for ordering lactate levels. Elevated serum lactate in a disease process that is limited to intracranial pathology underscores the systemic impact of high-grade SAH. As with other diseases, lactate levels are likely predictors of disease severity in patients with devastating neurologic diseases and should be collected. The first 24 hours is the most critical aspect of most critically ill patients. Serum lactate is readily and easily obtainable and may provide useful information on patient disease severity and mortality. Additional prospective data are needed to validate this finding and identify potential cutoff points for prognostication. The study is retrospective analysis of a prospective database and therefore has inherent limitations. Missing data on Hunt and Hess scales and Fisher scales as well as severity of injury scales were collected retrospectively. The location of the aneurysm on angiogram was not recorded. The sample size precludes a mortality assessment by aneurysm location, and we do not believe that serum lactate is a sensitiveenough indicator to identify mortality based on aneurysm location independent from severity of disease. A significant limitation of our study is that not all patients received lactate levels. We are unable to determine with a high degree of certainty why different physicians ordered lactate levels and others did not. However, we postulated that lactate levels were drawn on patients who presented with a higher degree of illness. Our conjecture is derived from an analysis of the groups who had lactate levels drawn vs the group who did not. Table 2 demonstrates that there were no differences in demographics between the 2 groups, whereas there is a significant difference in GCS, APACHE II, and mean arterial blood pressure, all validated measures of disease severity. We believe that the differences in the patients with lactate levels compared with those not drawn show a bias toward the more severe patients on presentation having lactate levels drawn. The general markers of disease severity noted in Table 2 and further substantiated in Table 3 support our presumption that lactate levels were preferentially drawn on the higher-acuity patients. Table 3 compares well-validated markers of neurologic injury specific to SAH, the modified Fisher scale and the Hunt and Hess scales, and the group with the worse modified Fisher and Hunt and Hess scales had lactate levels drawn. In addition, we do not have data on lactate levels as a function of time from the onset of SAH. Lactate levels have been shown to be a marker of disease severity in other disease states and are reasonable to believe that it may also be representative of disease severity in SAH patients as well. Thirty-one percent of patients who died did not have serum lactate levels drawn, and therefore, no information on 31% of these patients is known. However, the severity scales have been well-established markers of mortality and the correlation of lactate with these markers (Fig. 1) supports our findings.
5. Conclusion In aneurysmal SAH, elevated lactic acid levels on admission may have a predictive role. Currently, lactic acid levels are not ordered on all patients with SAH but perhaps should be part of the routine initial blood work and may serve as an additional prognostic marker. Prospective studies on the predictive ability of serum lactate on mortality are needed to validate these findings.
References [1] Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med 2006;354:387–96. [2] Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 1997;28:491–9. [3] Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25–146. [4] Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003;2:43–53. [5] Johnston SC, Colford Jr JM, Gress DR. Oral contraceptives and the risk of subarachnoid hemorrhage: a meta-analysis. Neurology 1998;51:411–8. [6] Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360:1267–74. [7] Ryttlefors M, Enblad P, Kerr RS, Molyneux AJ. International subarachnoid aneurysm trial of neurosurgical clipping versus endovascular coiling: subgroup analysis of 278 elderly patients. Stroke 2008;39:2720–6. [8] Kramer AH, Zygun DA. Declining mortality in neurocritical care patients: a cohort study in southern Alberta over eleven years. Can J Anaesth 2013;60:966–75. [9] Damian MS, Ben-Shlomo Y, Howard R, Bellotti T, Harrison D, Griggs K, et al. The effect of secular trends and specialist neurocritical care on mortality for patients with intracerebral haemorrhage, myasthenia gravis and Guillain-Barre syndrome admitted to critical care: an analysis of the Intensive Care National Audit & Research Centre (ICNARC) National United Kingdom Database. Intensive Care Med 2013;39: 1405–12. [10] Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997;28:660–4. [11] Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 1994;25: 1342–7. [12] Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med 2006;355: 928–39. [13] Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14–20. [14] Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, et al. A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 1988;51:1457. [15] Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ. Interobserver variability of grading scales for aneurysmal subarachnoid hemorrhage. Stroke 2011;42:1546–9. [16] Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6: 1–9.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
I.P. Aisiku et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx [17] Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly Jr ES, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified Fisher scale. Neurosurgery 2006;59:21–7 discussion 21-27. [18] Nyberg C, Karlsson T, Hillered L, Ronne EE. Metabolic pattern of the acute phase of subarachnoid hemorrhage in a novel porcine model: studies with cerebral microdialysis with high temporal resolution. PLoS One 2014;9:e99904. [19] Espiner EA, Leikis R, Ferch RD, MacFarlane MR, Bonkowski JA, Frampton CM, et al. The neuro-cardio-endocrine response to acute subarachnoid haemorrhage. Clin Endocrinol (Oxf) 2002;56:629–35. [20] Zetterling M, Engstrom BE, Hallberg L, Hillered L, Enblad P, Karlsson T, et al. Cortisol and adrenocorticotropic hormone dynamics in the acute phase of subarachnoid haemorrhage. Br J Neurosurg 2011;25:684–92. [21] Nagel A, Graetz D, Schink T, Frieler K, Sakowitz O, Vajkoczy P, et al. Relevance of intracranial hypertension for cerebral metabolism in aneurysmal subarachnoid hemorrhage. Clinical article. J Neurosurg 2009;111:94–101. [22] Hutchinson P, O'Phelan K, et al. International multidisciplinary consensus conference on multimodality monitoring: cerebral metabolism. Neurocrit Care 2014; 21(Suppl 2):S148–58. http://dx.doi.org/10.1007/s12028-014-0035-3. [23] Oddo M, Levine JM, Frangos S, Maloney-Wilensky E, Carrera E, Daniel RT, et al. Brain lactate metabolism in humans with subarachnoid hemorrhage. Stroke 2012;43: 1418–21. [24] Helbok R, Ko SB, Schmidt JM, Kurtz P, Fernandez L, Choi HA, et al. Global cerebral edema and brain metabolism after subarachnoid hemorrhage. Stroke 2011;42: 1534–9. [25] Gewirtz RJ, Dhillon HS, Goes SE, DeAtley SM, Scheff SW. Lactate and free fatty acids after subarachnoid hemorrhage. Brain Res 1999;840:84–91. [26] Barcelos GK, Tholance Y, Grousson S, Renaud B, Perret-Liaudet A, Dailler F, et al. Outcome of poor-grade subarachnoid hemorrhage as determined by biomarkers of glucose cerebral metabolism. Neurocrit Care 2013;18:234–44.
5
[27] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637. [28] Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, et al. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign Database. Crit Care Med 2015;43:567–73. [29] Maiuri F, Benvenuti D, Carrieri P, Orefice G, Carbone M, Carandente M. Serum and cerebrospinal fluid enzymes in subarachnoid haemorrhage. Neurol Res 1989;11:6–8. [30] Ruzak-Skocir B, Trbojevic-Cepe M. Study of serum and cerebrospinal fluid enzymes in diagnosis and differential diagnosis of cerebrovascular diseases. Neurologija 1990; 39:239–50. [31] Schlenk F, Vajkoczy P, Sarrafzadeh A. Inpatient hyperglycemia following aneurysmal subarachnoid hemorrhage: relation to cerebral metabolism and outcome. Neurocrit Care 2009;11:56–63. [32] Kruyt ND, Biessels GJ, de Haan RJ, Vermeulen M, Rinkel GJ, Coert B, et al. Hyperglycemia and clinical outcome in aneurysmal subarachnoid hemorrhage: a metaanalysis. Stroke 2009;40:e424–30. [33] Ahmadian A, Mizzi A, Banasiak M, Downes K, Camporesi EM, Thompson Sullebarger J, et al. Cardiac manifestations of subarachnoid hemorrhage. Heart Lung Vessels 2013;5:168–78. [34] Wybraniec MT, Mizia-Stec K, Krzych L. Neurocardiogenic injury in subarachnoid hemorrhage: a wide spectrum of catecholamin-mediated brain-heart interactions. Cardiol J 2014;21:220–8. [35] Chou SH, Robertson CS, Participants in the International Multi-disciplinary Consensus Conference on the Multimodality Monitoring. Monitoring biomarkers of cellular injury and death in acute brain injury. Neurocrit Care 2014. [36] Saritemur M, Akoz A, Kalkan K, Emet M. Intracranial hemorrhage with electrocardiographic abnormalities and troponin elevation. Am J Emerg Med 2013; 31(271):e275–7.
Please cite this article as: Aisiku IP, et al, Admission serum lactate predicts mortality in aneurysmal subarachnoid hemorrhage, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2015.12.079
