|Year : 2019 | Volume
| Issue : 3 | Page : 300-305
The effect of magnesium sulfate on cerebral perfusion in patients with sepsis-associated encephalopathy
Nesreen Shaban, Tamer Helmy, Samir Al Awady, Dina Zidan
Critical care medicine department, Faculty of Medicine, Alexandria University, Egypt
|Date of Submission||21-Jun-2018|
|Date of Acceptance||11-Mar-2019|
|Date of Web Publication||29-Aug-2019|
MS Critical Care Medicine Department. 01155550090
Source of Support: None, Conflict of Interest: None
Background Sepsis commonly produces brain cognitive dysfunction known as sepsis-associated encephalopathy (SAE).
Aim of the study The aim of this study was to assess the effect of administration of an intravenous bolus dose of magnesium sulfate on cerebral perfusion in patients with SAE.
Methods Using transcranial Doppler, we measured the mean flow velocity in the middle cerebral artery (cm/sec) and calculated the pulsatility index and resistive index on admission and 30 m after the administration of a 6 g intravenous dose of magnesium sulfate in septic patients with a positive Confusion Assessment Method for the ICU (CAM-ICU) score and Glasgow Coma Scale (GCS) less than 15 during the first 24 h from the onset of sepsis. The measurements were repeated after 24 h and were correlated with the GCS and CAM-ICU score of the patients after 24 h from the onset of sepsis.
Results Forty-six sepsis patients without any neurological deficit treated in our 14-bed Critical Care Unit [magnesium group (GroupMg)=23, control group (Groupcontrol)=23] were assessed. No difference was found between the two groups in mean age, mean arterial pressure or Acute Physiology and Chronic Health Evaluation II score. After 24 h, the pulsatility index was significantly reduced in the magnesium group (1.09±0.22, P<0.001) as well as the resistive index (0.62±0.07, P<0.001). Mean flow velocity was significantly higher in the magnesium group after 24 h (49.81±16.24, P<0.001). The magnesium group also displayed a significant improvement in the mean GCS after 24 h (11.65±1.99, P=0.048) and in the CAM-ICU score (negative CAM-ICU=16/23 patients, P≤0.001).
Conclusion Our results suggest that the administration of magnesium sulfate during the first 24 h of the onset of sepsis seems to improve cerebral perfusion in patients with SAE and possibly correlates with better neurological outcomes in these patients.
Keywords: cerebral microcirculation, encephalopathy, pulsatility index, resistance index, sepsis, cerebral vasoconstriction
|How to cite this article:|
Shaban N, Helmy T, Al Awady S, Zidan D. The effect of magnesium sulfate on cerebral perfusion in patients with sepsis-associated encephalopathy. Res Opin Anesth Intensive Care 2019;6:300-5
|How to cite this URL:|
Shaban N, Helmy T, Al Awady S, Zidan D. The effect of magnesium sulfate on cerebral perfusion in patients with sepsis-associated encephalopathy. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2020 May 24];6:300-5. Available from: http://www.roaic.eg.net/text.asp?2019/6/3/300/265719
| Methods|| |
This is a clinical prospective randomized observational study that was conducted on a total of 46 patients presenting to the Critical Care Department, Alexandria University, within the first 48 h of the onset of sepsis or septic shock during a 4-month period (July 2017–October 2017). Sepsis was defined according to the international criteria. A total of 23 patients received 6 g intravenous dose of magnesium sulfate within the first 6 h of initial resuscitation (magnesium group), and another 23 patients received only the standard management of sepsis (control group). Transcranial Doppler (TCD) was used to assess the flow velocities in the middle cerebral artery in both groups.
Approval of the Medical Ethics Committee of Alexandria Faculty of Medicine (serial number 0105101) and an informed consent from the patient’s next of kin were obtained before conducting the study.
Exclusion criteria for both groups were as follows: (a) age less than 18 years, (b) known cerebral lesion (ischemic or hemorrhagic cerebrovascular event, neoplasm), (c) central nervous system infection, (d) other causes of encephalopathy including uremia, hepatic encephalopathy, hyper/hyponatremia, hyper/hypoglycemia, (e) hepatic encephalopathy, (f) patient supported by Intra-Aortic Balloon Pump or by extracorporeal membrane oxygenation (ECMO), (g) nonsinusal rhythm, (h) known severe carotid stenosis (>70%), (i) history of extended cervical operation, and (j) pregnant female individuals.
Demographic data on all patients and diagnosis on ICU admission were recorded. The source of sepsis, relevant microbiological results, and treatments, including the administration of adrenergic and sedative agents, were recorded. The neurological status of all patients was assessed using the Glasgow Coma Scale (GCS) and the Confusion Assessment Method for the ICU (CAM-ICU) on admission and after 24 h. The severity of critical illness was assessed from the Acute Physiology and Chronic Health Evaluation II score.
Mean velocity in the middle cerebral artery (VmMCA) was measured using a 2 MHz TCD probe through the temporal bone window on both sides of the skull, on admission and after 24 h for both groups. Readings were also obtained 30 min after the administration of 6 g intravenous dose of magnesium sulfate in the magnesium group.
Administration of magnesium sulfate
Six grams of 1% magnesium sulfate was diluted in 150 ml of dextrose 5% and administered over 20 min at the end of the first 6 h of initial resuscitation.
The administration of MgSO4 was interrupted in case of (a) bradycardia (heart rate <45 beats/min); magnesium sulfate was entirely stopped in case of hemodynamic affection and need of atropine and (b) hypotension (systolic blood pressure <110 mmHg); the application of MgSO4 was interrupted and entirely stopped if the amount of norepinephrine/epinephrine had to be doubled or if a second catecholamine was needed to maintain the blood pressure above 110 mmHg, (c) atrioventricular conduction disturbances, asystole (>2 s), (d) respiratory failure suspected of being MgSO4 related, and (e) oliguria and/or severe fluid and electrolyte imbalance.
Each measurement on each side of the brain was repeated three times, and the highest value was considered for our analysis. The average of the two values on the two brain sides was registered. A difference in depth of 0.5 cm between the two sides was considered acceptable.
Pulsatility index (PI) (PI=velocity systolic–velocity diastolic/mean velocity) and cerebrovascular resistant index (RI) (RI=velocity systolic–velocity diastolic/velocity systolic) were calculated .
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0 (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, SD and median. Significance of the obtained results was judged at the 5% level .
| Results|| |
Forty-six patients presenting with sepsis/septic shock were enrolled in the study. Twenty-three patients received intravenous magnesium sulfate within the first 6 h of initial resuscitation (GroupMg), and 23 patients received only the standard management of sepsis (Groupcontrol). There was no significant difference between both groups in terms of age (GroupMg: 66.04±9.80; Groupcontrol: 69.57±8.29, P=0.195) or Acute Physiology and Chronic Health Evaluation II score (GroupMg: 20.13±4.08, Groupcontrol: 19.61±4.29, P=0.675). All patients presented with a positive CAM-ICU score. There was no significant difference between both groups in the mean GCS on admission (GroupMg: 10.52±2.56, Groupcontrol: 10.70±2.40, P=0.813).
Mean arterial blood pressure (MAP, mmHg) was not significantly different between both groups on admission (GroupMg: 86.80±5.29, Groupcontrol: 86.00±5.29, P=0.611). The percentage of patients who were evaluated while on norepinephrine was similar in both groups (60.9 vs. 56.5%, P=0.765).
Pneumonia was the most common cause of sepsis in both groups (52.1% in both groups) followed by urinary tract infections.
On admission, both groups demonstrated elevated PI and resistive index (RI), with no statistically significant difference between the groups. The mean PI in GroupMg was 1.55±0.36 and in Groupcontrol it was 1.56±0.15 (P=0.953). As for the RI, the mean RI was 0.75±0.12 and 0.76±0.04 for GroupMg and Groupcontrol, respectively (P=0.930). There was no statistically significant difference in the VmMCA (cm/s) between both groups on admission (GroupMg: 40.88±9.64, Groupcontrol: 41.17±5.36, P=0.741).
[Table 1] illustrates the change in PI after administration of magnesium sulfate in the magnesium group. A significant reduction was noted, with the mean PI falling from 1.55±0.36 to 1.14±0.29 (P<0.001) 30 min after the administration of magnesium sulfate. A further reduction was noted after 24 h (mean PI: 1.09±0.22, P<0.001).
|Table 1 Comparison between the pulsatility index in GroupMg before and after the administration of magnesium sulfate|
Click here to view
A significant reduction was also noted in the RI in the magnesium group (admission: 0.75±0.12, 30 min after MgSO4: 0.64±0.11, P=0.002). After 24 h, the value dropped to 0.62±0.07 (P<0.001) ([Figure 1] and [Figure 2], [Table 2]).
|Figure 1 Comparison between the pulsatility index in GroupMg before and after the administration of magnesium sulfate.|
Click here to view
|Figure 2 Comparison between the resistive index before and after the administration of magnesium sulfate in Groupcontrol.|
Click here to view
|Table 2 Comparison between the resistive index in GroupMg before and after the administration of magnesium sulfate|
Click here to view
VmMCA was significantly increased 24 h after the administration of magnesium sulfate (40.88±9.64; 24; 49.81±16.24, P=0.003).
[Table 3] illustrates the changes noted in the PI, RI, and VMCA in both groups over the study period. On admission, there was no statistically significant difference between the PI, RI, and VmMCA in both groups. After 24 h, the magnesium group demonstrated a significant reduction in the mean PI and RI values, along with a significant increase in the VmMCA.
|Table 3 Comparison between the pulsatility index, resistive index, and mean flow velocity in the middle cerebral artery between both groups on admission and after 24 h|
Click here to view
Our study also noted a significant improvement in the mean GCS and CAM-ICU score in the magnesium group after 24 h compared with the control group. Sixteen of 23 patients in the magnesium group turned CAM-ICU negative compared with 11 patients in the control group (P<0.001), while the mean GCS was 11.65±1.99 and 10.26±2.60, respectively (P=0.048) ([Figure 3]).
|Figure 3 Comparison between the two studied groups according to CAM-ICU score on admission and after 24 h. CAM-ICU, Confusion Assessment Method for the ICU.|
Click here to view
| Discussion|| |
The most important finding of this study was the significant reduction in the PI and RI values following the administration of magnesium sulfate. This was associated with a significant improvement in the GCS and CAM-ICU score after 24 h.
The reduction in the pulsatility and RIs, along with the increase in the VmMCA, suggest that global cerebral perfusion improved following the administration of magnesium sulfate. Possible explanations could be concluded from previous studies that documented the neuroprotective effects of magnesium sulfate in various clinical settings.
Our results were in concordance with the conclusion of a study conducted by Esen et al. . They deduced that sepsis affects the BBB permeability, leading to brain edema in animal models of sepsis. Moreover, disruption of the BBB allows high levels of endogenous catecholamines to directly influence cerebrovascular resistance. Both mechanisms eventually lead to a reduced cerebral blood flow and reduced oxygen delivery .
In Esen’s study, magnesium sulfate administration was found to decrease the increased BBB permeability and caused a reduction in brain edema formation. The precise mechanism is unknown, but it has been suggested that magnesium can affect many aspects of the neuromediator cascade that can lead to a permeability defect in the BBB, in addition to directly acting on the BBB through suppression of endothelial cells. These cells are activated early in sepsis, and they release proinflammatory mediators and facilitate nitric monoxide release in the brain, initiating or activating the cerebral inflammatory process. The ensuing edema and neutrophil and platelet accumulation within the cerebral microvessels have been associated with impairment of cerebral microcirculation. In addition, the premature activation of these cells by inflammatory cytokines and endotoxins can decrease the endothelium vasoactive response through nitric oxide (NO), allowing vasoconstriction mediated by prostanoids and endothelins .
Moreover, Belfort and Moise concluded that the PI in the middle cerebral artery was significantly reduced in patients who suffered from pre-eclampsia following the administration of 6 g intravenous bolus of magnesium sulfate (change in PI=−0.16±0.09, P=0.01) . In pre-eclampsia, reviews explain that the pathogenesis may be related to maternal endothelial cell damage initiated by the release of substances from a hypoperfused placenta. The changes in endothelial cell injury set in motion a dysfunctional cascade of coagulation, vasoconstriction, and intravascular coagulation, leading to increased cerebral vascular resistance. A similar mechanism has been suggested as an explanation for the pathogenesis of SAE .
Magnesium sulfate was also found to be effective in the management of Posterior Reversible Encephalopathy Syndrome (PRES) . PRES is a clinicoradiological syndrome associated with headache, convulsions, altered mental status, and visual loss, and it is radiologically characterized by white matter vasogenic edema affecting the posterior occipital and parietal lobes of the brain predominantly. This syndrome has been described in patients presenting with sepsis, as demonstrated by Bartynski et al. , who reported the presence of PRES in 25 of 106 patients presenting with infection, sepsis, and shock (23.6%).
Pandita and colleagues describe a case of nonresolving PRES syndrome in a 38-year-old male patient presenting with multiorgan dysfunction from tricuspid valve infective endocarditis, peritonitis, and pelvic abscess. Clinical condition of the patients was improve after administration of 4 g magnesium sulfate, with a return to his baseline condition within 1 week of the initiation of therapy with magnesium sulfate without any neurological deficits .
Possible confounding factors that may have affected the results of the study were the systemic MAP and the use of vasopressors. There was no statistically significant difference between the MAP on admission and after 24 h between the two groups. In GroupMg, having a mean MAP of 86.00±5.29 mmHg on admission and 87.56±5.20 mmHg after 24 h did not seem to have favorable results on the neurological outcome of these patients. In an experimental study conducted by Bowton et al. , changes in cerebral blood flow in sepsis models did not correlate with alterations in MAP. In addition, cerebral microvascular alterations, along with impaired cerebral autoregulation and impaired vasomotor reactivity, were found to be independent from systemic hemodynamics in affecting cerebral blood flow in sepsis, as described by Belfort et al., Pierrakos et al., and Kaya et al. ,,.The use of vasopressors in our study did not show significant effects on the results. These findings are in accordance with a study conducted by Burkhart et al. , wherein the cerebral effects of vasopressors in sepsis were found to be independent to the degree of blood brain barrier (BBB) dysfunction.
Overall, the results of this study suggest that the administration of magnesium sulfate to patients presenting with SAE within the first 24 h of sepsis seems to have a favorable outcome on the measured cerebral blood flow velocities and can be linked to a better neurological outcome in patients with SAE .
Limitations of this study include the following (and they are): (a) the sample size was relatively small, (b) TCD readings were only obtained over the course of 2 days; we suggest assessing the MCA velocities beyond the 2 days stated in this study to determine whether the observed variations in TCD were transient or persisted throughout the course of sepsis, and (c) a single dose of magnesium was used. We recommend assessing the effect of different doses of magnesium sulfate in order to determine whether the observed changes are dose dependent, what is the optimal dose that can be safely used in these patients in order to avoid the potential side effects of the drug and the optimal time for administration of the drug.
| Conclusion|| |
The administration of magnesium sulfate to patients presenting with SAE within the first 24 h of sepsis seems to have a favorable outcome on the measured cerebral blood flow.
Both the pulsatility and RIs in the middle cerebral artery were significantly reduced, and this was associated with a significant improvement in the neurological outcome of the patients in terms of the GCS and CAM-ICU score.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lindenauer P. Utilization patterns and outcomes associated with central venous catheter in septic shock: a population-based study. Crit Care Med 2013; 41:1450–1457. Doi: 10.1097/CCM.0b013e31827caa89
Bleck TP, Smith MC, Pierre-Louis SJ, Jares JJ, Murray J, Hansen CA. Neurologic complications of critical medical illnesses. Crit Care Med 1993; 21:98–103.
Eidelman LA, Putterman D, Putterman C, Sprung CL. The spectrum of septic encephalopathy: definitions, etiologies, and mortalities. JAMA 1996; 275:470–473.
Barichello T, Martins MR, Reinke A, Feier G, Ritter C, Quevedo J et al.
Long-term cognitive impairment in sepsis survivors. Crit Care Med 2005; 33:1671.
Howells T, Elf K, Jones PA, Ronne-Engström E, Piper I, Nilsson P et al.
Pressure reactivity as a guide in the treatment of cerebral perfusion pressure in patients with brain trauma. J Neurosurg 2005; 102:311–317.
Rosengarten B, Wolff S, Klatt S, Schermuly RT. Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model. Crit Care 2009; 13:R139.
Mihaylova S, Killian A, Mayer K, Pullamsetti SS, Schermuly R, Rosengarten B. Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats. J Neuroinflammation 2012; 9:183.
Belfort MA, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomized, placebo-controlled study. Am J Obstet Gynecol 1992; 167:661–666.
Pierrakos C, Attou R, Decorte L, Kolyviras A, Malinverni S, Gottignies P et al.
Transcranial Doppler to assess sepsis-associated encephalopathy in critically ill patients. BMC Anesthesiol 2014; 14:45.
Kirkpatrick LA, Feeney BC. A simple guide to IBM SPSS: for version 20.0. 12 ed. Belmont, CA: Wadsworth Publishing; 2012; 128.
Azevedo DS, de, Salinet ASM, Oliveira M, de L, Teixeira MJ, Bor-Seng-Shu E et al.
Cerebral hemodynamics in sepsis assessed by transcranial Doppler: a systematic review and meta-analysis. J Clin Monit Comput 2016; 1–10.
Esen F, Erdem T, Aktan D, Kalayci R, Cakar N, Kaya M et al.
Effects of magnesium administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats. J Neurosurg Anesthesiol 2003; 15:119–125.
Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc 2010; 85:427–432.
Bartynski WS, Boardman JF, Zeigler ZR, Shadduck RK, Lister J. Posterior reversible encephalopathy syndrome in infection, sepsis, and shock. Am J Neuroradiol 2006; 27:2179–2190.
Pandita A, Chaudhary O, Sexton J. Treatment of non resolving posterior reversible encephalopathy syndrome (PRES) with magnesium sulphate. in: a55 critical care case reports: neuro critical care and toxicology [Internet]. Am J Resp Crit Care Med 2016; 193:A1922.
Bowton DL, Bertels NH, Prough DS, Stump DA. Cerebral blood flow is reduced in patients with sepsis syndrome. Crit Care Med 1989; 17:399–403.
Kaya M, Küçük M, Kalayci RB, Cimen V, Gürses C, Elmas I et al.
Magnesium sulfate attenuates increased blood-brain barrier permeability during insulin-induced hypoglycemia in rats. Can J Physiol Pharmacol 2001; 79(9):793–798.
Burkhart CS, Siegemund M, Steiner LA. Cerebral perfusion in sepsis. Crit Care 2010; 14:215.
Westermaier T, Stetter C, Kunze E, Willner N, Raslan F, Vince GH et al.
Magnesium treatment for neuroprotection in ischemic diseases of the brain. Exp Transl Stroke Med 2013; 5:6.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]