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Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 50-54

Pathophysiology of brain stem death

Department of Anesthesia, Amrita Institute of Medical Science, Kochi, Kerala, India

Date of Submission03-May-2020
Date of Acceptance05-May-2020
Date of Web Publication18-Aug-2020

Correspondence Address:
Dr. Eldo Issac
Department of Anesthesia, Amrita Institute of Medical Science, Kochi, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AMJM.AMJM_32_20

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Brain stem death (BD) is a pathological process which has a profound effect on hemodynamic balance, hormone levels and functioning of other organ systems. It also triggers a systemic inflammatory response. Knowledge about the changes that occur during brain stem death is necessary for subsequent management. This article discusses the pathophysiological changes in the body after brain stem death.

Keywords: Brain stem death, pathophysiology, sympathetic storm

How to cite this article:
Issac E, Venugopalan S. Pathophysiology of brain stem death. Amrita J Med 2020;16:50-4

How to cite this URL:
Issac E, Venugopalan S. Pathophysiology of brain stem death. Amrita J Med [serial online] 2020 [cited 2023 Mar 26];16:50-4. Available from: https://ajmonline.org.in/text.asp?2020/16/2/50/292428

  Introduction Top

Brain stem death (BD) is a pathological process which is characterized by hormonal impairment, hemodynamic imbalance, and a systemic inflammatory response. Knowledge about these changes is important in managing a BD donor. Three main causes of BD include traumatic brain injury (TBI), cerebrovascular injury, and anoxia. The cause of death has a significant impact on recipient survival rates, though this can vary according to the organ. Renal transplant is affected by cerebrovascular causes, whereas lung transplant is unaffected by the cause of death, while heart transplant outcomes remain controversial.[1] For this reason, it is important to consider the pathophysiologic responses to central nervous system (CNS) injury, and their systemic sequelae, before BD.

The American Academy of Neurology defines BD as the irreversible loss of brain and brain stem function, usually caused by major hemorrhage, hypoxia, or metabolic dysregulation. The diagnosis is based on a comprehensive neurologic assessment with the absence of brain stem reflexes and apnea under standardized conditions (blood alcohol content: 0.08%, core temperature: 36°C, systolic blood pressure: 100 mmHg, and exclusion of CNS depressant drugs).[2] Ancillary tests, such as electroencephalography, transcranial doppler-ultrasound, or cerebral angiography, are required in cases of uncertainty of the clinical examination. Incidence of physiologic changes after brain stem death is shown in [Table 1].
Table 1: Incidence of physiologic changes after brain stem death

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Cushing reflex is characterized by bradycardia and systemic arterial hypertension and can be seen in a BD patient due to rise in intracranial pressure (ICP). Rise in intracerebral hemorrhage (ICH) causes overwhelming sympathetic stimulation which causes catecholamine storm, which in turn causes severe vasoconstriction leading to end-organ dysfunction. High intracranial pressure causes cerebral and brain stem herniation which leads to sympathetic stimulation and dysfunction of the hypothalamo-pituitary axis. This in turn causes hypotension and also reduces levels of circulating ADH, thyroid hormones and cortisol. Ischemia leads to metabolic acidosis which stimulates the releases of cytokines and activates coagulation factors and promotes leukocytic proliferation, causing systemic inflammatory pathway activation and tissue damage. Interaction of homeostatic mechanisms after brain stem death is given in [Figure 1].
Figure 1: Interaction of homeostatic mechanisms after brain stem death. ALI: Acute lung injury, AM: Alveolar macrophage, ARDS: Acute respiratory distress syndrome, CaO: Arterial oxygen content, BBB: blood brain barrier, BS: Brain stem, CHO: Carbohydrate, CNS: Central nervous system, CO: Cardiac output, DO: Oxygen delivery, NPO: Neurogenic pulmonary edema, PNS: Parasympathetic nervous system, PVR: Pulmonary vascular resistance, ROS: Reactive oxygen species

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  Autonomic Nervous System (Ans) Top

Brain stem failure leads to initial hypertension and bradycardia followed by an intense “sympathetic storm” which remains unopposed due to ischemia of the parasympathetic vagal nucleus and occurs in a rostrocaudal direction. This storm results in release of catecholamines in an attempt to perfuse the brain (increases mean arterial pressure [MAP]) to overcome the elevated ICP. Such changes in sympathetic outflow can be detected before the occurrence of BD. The massive increase in sympathetic tone results in widespread vasoconstriction and microthrombus formation, which in turn impairs organ and tissue perfusion. Ischemia progresses down the brain stem and the sympathetic centers become necrotic, vascular, and myocardial sympathetic stimulation drops and a second phase of hypotension ensues, as the ICP outpaces the MAP. Uncontrolled hypotension further impairs end-organ perfusion that resulted during the sympathetic storm. Even though the effects of the sympathetic nervous system are seen clinically during and after BD, inflammatory and hemodynamic responses are also influenced by the parasympathetic nervous system (PNS). Vagal stimulation directly decreases inflammation through cholinergic receptors on inflammatory cells. PNS through interleukin (IL-1) receptors in the parasympathetic ganglia interacts with innate immunity system through a negative feedback mechanism and maintains the balance.[3],[4]

Acetylcholine, the primary parasympathetic neurotransmitter, binds with both nicotinic and muscarinic receptors. Nicotinic cholinergic receptor found on macrophages is the a7 subunit, on activation leads to inhibition of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), and causes downregulation in the production of pro-inflammatory cytokines. Acetylcholine also can dampen inflammatory responses by inhibiting high mobility group box 1 release by activated macrophages, which is pro-inflammatory. The pathways that are most significantly affected by vagal stimulation are the leukocyte-transendothelial migration pathway, the cytokine–cytokine receptor pathway, the focal adhesion pathway, and the Toll-like receptor pathway. Vagus nerve stimulation decreases the release of cytokines, chemokines, adhesion molecules, extracellular matrix components, and signaling molecules. Vagus nerve stimulation diversely affected gene expression in donor organs and improved renal function in allografts. BD inhibits PNS-mediated anti-inflammatory responses by direct destruction of vagal centers in the brain stem.

  Cardiovascular System Top

Several authors have described the cardiovascular changes that takes place after brain stem death.[5],[6] Myocardial dysfunction is thought to occur at an incidence of 50%–90% following brain injury. Catecholamine storm enhances beta-adrenergic stimulation which interns induced coronary vasoconstriction leading to schema and arrhythmia. The pathophysiology of cardiac dysfunction after BD remains controversial. There are two scenarios:

Catecholamine hypothesis

The storm

BD is frequently accompanied by massive release of endogenous catecholamines (catecholamine storm). An increase in sympathetic tone either through adrenal medullary axis or due to increased activation of sympathetic innervation of heart, with excessive catecholamine release systemically and within the myocardium, can occur due to stimulation of cortical areas. It is well recognized that high sympathetic tone and elevated circulating levels of catecholamines may occur after head injury.

High catecholamine levels

High levels of norepinephrine in the myocardial interstitium lead to myocyte necrosis and contractile dysfunction and damage the sympathetic nerve terminals themselves. Brain injury may also cause neuronal degeneration at the origin of sympathetic outflow to the heart, especially at the insula or hypothalamus. The electrocardiogram and echocardiographic findings in some patients with subarachnoid hemorrhage suggested coronary vasospasm due to catecholamine surge.

Mechanisms of myocardial cell death

The reduction in calcium ATPase activity leads to myocyte calcium overload and cell death, which occurs due to the high interstitial concentration of norepinephrine. Some authors believe that the massive catecholamine “storm” may produce coronary artery spasm which impairs myocardial perfusion, resulting in necrosis of the subendocardium, petechial hemorrhage, contraction bands, and coagulative myocytolysis. Bittner et al. suggest that the biventricular injury occurred during the hyperdynamic response when systolic blood pressure increased to more than 500 mmHg while systemic as well as pulmonary vascular resistance doubled. This may have resulted in cardiomyocyte injury and subsequent biventricular distension leading to altered Frank–Starling mechanism as reflected by an increase in right and left end-diastolic pressures and a decrease in stroke work.

The clinical consequences

These lead to donor cardiac dysfunction as well as neurogenic pulmonary edema.

Novitsky hypothesis

According to this hypothesis, cardiac dysfunction is caused by two separate physiologic processes. First, it is due to catecholamine surge during the initial neurologic insult (myocardial dysfunction due to “neural phase”) and second due to several metabolic perturbations (myocardial dysfunction due to “humoral phase”). Severe harmonic derangements are observed after BD. Eventually, anaerobic metabolism causes increased tissue acidosis and loss of myocardial energy stores. The inflammatory response is accelerated with rapid expression of cytokines, chemokines, and adhesion molecules and leukocyte infiltration. The upregulation of major histocompatibility Class II antigens increases organ immunogenicity.

  Pulmonary System Top

  1. The hemodynamic mechanism: Catecholamine storm results in massive rise of pulmonary capillary pressure
  2. The sympathetic alteration of capillary permeability (catecholamine storm) causes increased protein and fluid flux across the capillary endothelium
  3. Humoral and cellular pathways are activated leading to cytokine upregulation, endothelial expression molecules, and neutrophil infiltration leading to tissue damage.

  Encocrine System Top

BD causes cessation of the hypothalamic–pituitary axis and affects hormone regulation.[7] Rapid depletion of ADH causes diabetes insipidus (DI) in 80% of BD donors. DI is characterized by inappropriate diuresis with associated hypovolemia, hyperosmolarity, and hypernatremia. Many studies have revealed conflicting results with regard to cortisol secretion with the various studies describing cortisol levels as normal, low, or high. However, absolute cortisol levels may not be the appropriate measure of the function of the Hypothalamic-Pituitary Adrenal axis (HPAa).

Nonthyroidal illness syndrome (NTIS) can be seen in BD donors, which may confound the metabolic state. It is yet to be proven that whether hormone supplementation to correct this deficiency is beneficial. The biochemical changes observed in NTIS include modifications of the hypothalamic–pituitary thyroid axis, altered binding of TH to circulating proteins, modified entry of TH into tissues, changes in TH metabolism due to modification of the iodothyronine deiodinases as well as changes in TH receptor expression or function. T3 concentrations fall to approximately 50% of normal within 24 h of BD and stabilize to approximately 40% over the next 7 days.

Female sex hormone concentrations rapidly decreased after BD, probably due to cessation of the hypothalamic–pituitary–ovary axis.[8] Sudden decreases in estradiol and progesterone levels may affect the control of several nonreproductive tissues. Without inducing functional alterations, sex hormones may also impact white cell subpopulations and delay neutrophil apoptosis. Females have better outcomes than males after shock, trauma, and sepsis because sex hormones play a key role in the protection afforded by female sex in various trauma models.

  Immunological And Complement Activation Top

The biological processes related with transcription (such as regulation of transcription, DNA dependent, and positive regulation of transcription) and metabolic process (such as regulation of phosphate metabolic process and regulation of phosphorus metabolic process) were dysregulated in the liver after BD.[9] Inflammatory response is controlled by the transcription factors, transcriptional coregulators, and chromatin modification. This also triggers the transcription of inflammatory cytokine genes that increase the inflammatory response.[10] These elevated cytokines after injury accelerate the metabolic derangement and organ dysfunction. The downregulated genes may play major roles in organ function decrease.

BD is associated with increased complement activation, apoptosis, and pro-inflammatory cytokine and plays an important role in graft rejection.[10],[11] Autonomic storms not only increase lymphokine and cytokine expression but also upregulate major histocompatibility complex Class I and II antigens. Studies showed that the co-stimulatory molecule B7 is upregulated in peripheral organs including the kidney, heart, liver, and spleen. Macrophage- and Th1-associated cytokine expression increases progressively in a time-dependent manner during an autonomic storm. Chemokines and cytokines help to control the selective migration and activation of inflammatory cells.

IL-13, tissue inhibitor of metalloproteinase 1 (TIMP-1), and CXCL3 are important cytokines that are released from the liver which are a significant component of the acute-phase response associated with CNS injury. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that can degrade extracellular matrices. Almost all MMPs share similar characteristics and are inhibited by TIMPs. TIMPs influence biological processes such as cell growth, apoptosis, differentiation, angiogenesis, and oncogenesis. TIMP-1 inhibits signaling pathways that regulate cell division in humans and animals, and these cytokine levels are increased sharply during BD and remained high. This trend of elevated TIMP-1 levels may be explained by its angiogenesis inhibitor function.

LCN2 is also known as neutrophil gelatinase-associated lipocalin which increases rapidly following liver injury which is produced by the injured hepatocytes, and recent studies further indicate that LCN2 is a reliable indicator of liver damage. LCN2 might also serve as a sensitive marker for hepatic inflammation following BD.

BD influences NK cells and results in clear maturation of splenic NK cells. We can only speculate on the biological relevance and impact of this BD-related effect, but it appears that NK cells were differently affected depending on the varying immunological profile of solid organs after the onset of BD and transplantation. Nevertheless, further studies are needed to clarify their potential role in BD-related pathology.

Newer studies showed that the association between resistin and MCP-1 in the brain stem dead organ donors seems to indicate a causative relationship between these two and may suggest a role for resistin in the initiation of the inflammatory response after brain death.[12] The increase in resistin levels reflects the inflammatory state after BD. Although the receptor for resistin is still disputed, it is shown that the signaling occurs mainly through the NF-κB pathway. This is a pro-inflammatory pathway involved in the synthesis and secretion of numerous pro-inflammatory cytokines

Recent studies have shown that concentrations of serum S100B protein in brain stem dead organ donors are extremely high and may support the diagnosis of brain stem death.[13] S100B can be used as a diagnosing tool to access CNS damage resulting from different etiologies. Diagnosis is based on the role of S100B, which is a protein of astrocyte-like glia. These cells participate in astrocyte proliferation as well as interactions between the glia and surrounding nervous tissue. The release of S100B protein from a glia induces apoptosis through the production of nitric oxide, which results in blood–brain barrier damage, which is observed in each case of brain structure damage. Measurement of S100B protein concentrations could be extremely important in patients with spinal and pupillary reflexes.

  Coagulopathy Top

The severely disturbed von Willebrand factor (VWF)/ A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) balance seen in the BD organ donor may also point to an increased capacity for systemic unregulated generation of microthrombi, as it occurs in patients with a complete deficiency of ADAM-TS13.[14] The increased VWF propeptide levels in the brain stem dead organ donors are due to an acute activation of the endothelium. Increased levels of D-dimer are consistent with a prothrombotic status. A hypofibrinolytic state, as indicated by elevated clot lysis times and elevated plasma levels of PAI-1, suggests that the clots generated are cleared less efficiently.

This apparent paradox may be explained in several ways. In one scenario, even though clot lysis occurs, the net accumulation of fibrin occurs due to insufficient clearance of fibrin that is generated. This theory is compatible with the observations of fibrin-rich clots in organs of brain stem dead donors. In a second scenario, endogenous tissue plasminogen activator (TPA) mediated fibrinolysis contributes little to the lysis of fibrin clots. Instead, it is mediated by other activators of plasminogen, which are generated in pathological situations.

  Others Top

Delayed gastric emptying causes problems such as gastric distention, nutritional intolerance, gastroesophageal reflux disease, and pulmonary aspiration.[15] Normal gastric slow waves (<70%) that are seen in comatose patients can be demonstrated in BD patients. TBI damages jejunal structure and barrier function that can occur as early as 3 h after brain injury. Potent mediators of the induction of adhesion molecules and selectins are pro-inflammatory cytokines, such as TNFα, IL-1, IL-18. Early occurrence of intestinal inflammation and apoptosis after BD induction have also been reported, which may ultimately have a negative influence on the outcome of intestinal transplantation.[16]

Occasionally, diverse types of spinal reflexes and automatisms are encountered in BD.[17] These are plantar withdrawal responses, muscle stretch reflexes, abdominal contractions, slow turning of the head to one side, Lazarus sign (shoulder adduction, crossing both arms on the chest, moving hands to the neck, and finally falling to the bed), respiratory-like movements, facial myokymia, finger jerks, periodic limb movements, and automatic stepping.

  Conclusion Top

BD can affect other organs and results in multi-organ failure. It is important to know about the pathophysiology of BD, as it helps in subsequent management.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Watts RP, Thom O, Fraser JF. Inflammatory signalling associated with brain dead organ donation: From brain injury to brain stem death and posttransplant ischaemia reperfusion injury. J Transplant 2013;2013:521369.  Back to cited text no. 1
Floerchinger B, Oberhuber R, Tullius SG. Effects of brain death on organ quality and transplant outcome. Transplant Rev (Orlando) 2012;26:54-9.  Back to cited text no. 2
Hoeger S, Bergstraesser C, Selhorst J, Fontana J, Birck R, Waldherr R, et al. Modulation of brain dead induced inflammation by vagus nerve stimulation. Am J Transplant 2010;10:477-89.  Back to cited text no. 3
Essien EO, Fioretti K, Scalea TM, Stein DM. Physiologic features of brain death. Am Surg 2017;83:850-4.  Back to cited text no. 4
Paweł Chudoba1 A, Wojciech Krajewski CD. Joanna wojciechowska brain death-associated pathological events and therapeutic options. Adv Clin Experimental Med 2017;26:1457-146.  Back to cited text no. 5
Apostolakis E, Parissis H, Dougenis D. Brain death and donor heart dysfunction: Implications in cardiac transplantation. J Card Surg 2010;25:98-106.  Back to cited text no. 6
Ranasinghe AM, Bonser RS. Endocrine changes in brain death and transplantation. Best Pract Res Clin Endocrinol Metab 2011;25:799-812.  Back to cited text no. 7
Breithaupt-Faloppa AC, Ferreira SG, Kudo GK, Armstrong R Jr., Tavares-de-Lima W, da Silva LF, et al. Sex-related differences in lung inflammation after brain death. J Surg Res 2016;200:714-21.  Back to cited text no. 8
Liu Q, Ye Q. Computationally prediction of candidate agents for preventing organ dysfunction after brain death. Ann Transplant 2016;21:301-10.  Back to cited text no. 9
Esmaeilzadeh M, Sadeghi M, Galmbacher R, Daniel V, Knapp J, Heissler HE, et al. Time-course of plasma inflammatory mediators in a rat model of brain death. Transpl Immunol 2017;43-44:21-6.  Back to cited text no. 10
Ritschl PV, Ashraf MI, Oberhuber R, Mellitzer V, Fabritius C, Resch T, et al. Donor brain death leads to differential immune activation in solid organs but does not accelerate ischaemia-reperfusion injury. J Pathol 2016;239:84-96.  Back to cited text no. 11
Oltean S, Pullerits R, Flodén A, Olausson M, Oltean M. Increased resistin in brain dead organ donors is associated with delayed graft function after kidney transplantation. J Transl Med 2013;11:233.  Back to cited text no. 12
Krzych ŁJ, Czempik PF, Saucha W, Kokocińska D, Knapik P. Serum S100B protein concentration in brain-dead organ donors: A pilot study. Anaesthesiol Intensive Ther 2015;47:320-3.  Back to cited text no. 13
Lisman T, Leuvenink HG, Porte RJ, Ploeg RJ. Activation of hemostasis in brain dead organ donors: An observational study. J Thromb Haemost 2011;9:1959-65.  Back to cited text no. 14
Bor C, Bordin D, Demirag K, Uyar M. The effect of brain death and coma on gastric myoelectrical activity. Turk J Gastroenterol 2016;27:216-20.  Back to cited text no. 15
Koudstaal LG, 't Hart NA, Ottens PJ, van den Berg A, Ploeg RJ, van Goor H, et al. Brain death induces inflammation in the donor intestine. Transplantation 2008;86:148-54.  Back to cited text no. 16
Beckmann YY, Ciftçi Y, Seçil Y, Eren S. Fasciculations in brain death. Crit Care Med 2010;38:2377-8.  Back to cited text no. 17


  [Figure 1]

  [Table 1]

This article has been cited by
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