Abstract
Evidence-based practice involves conscientious decision-making, which is based on the best available evidence as well as preferences and patient characteristics. Neuroanesthesiology is a rapidly growing superspecialty branch of medicine that has achieved remarkable growth in neuroanesthetic techniques and management. Despite achievements controversies persist. Most of the multicenter trials conducted provide results that have little clinical significance. Most randomized controlled trials focus on surrogate endpoints rather than clinical or neurologic outcomes. Some of the common issues related to the practice of neuroanesthesia are discussed in this chapter.
Keywords
Anesthesia, Brain protective strategies, Brain Trauma Foundation guidelines, Decompressive craniectomy, Evidence-based practice, Neuroanesthesia, Target intracranial pressure
Outline
Introduction 881
Evidence-Based Practice and Neuroanesthesia 883
Target Intracranial Pressure and Cerebral Perfusion Pressure 883
Effect of Inhalational Anesthetics on Intracranial Pressure 883
Effect of Intravenous Anesthetics on Intracranial Pressure 883
Effect of Hyperventilation and Positive End Expiratory Pressure on Intracranial Pressure 884
Effect of Hyperosmolar Therapy on Intracranial Pressure 884
Effect of Various Positions on Intracranial Pressure 884
Effect of Decompressive Craniectomy on Intracranial Pressure 884
Fluid Therapy in Neurosurgical Patients 885
Evidence for Brain Protective Strategies 885
Hypothermia 885
Glycemic Control 885
Steroids 885
Mean Arterial Pressure 886
Inhalational Agents 886
Intravenous Agent 886
Magnesium (Mg2 + ) 886
Dexmedetomidine 886
Evidence and the Brain Trauma Foundation Guidelines 887
Unresolved Issues in the Practice of Neuroanesthesia 887
Conclusion 887
Clinical Pearls 889
References 889
Introduction
It was in the year 1992 that evidence-based practice (EBP) was formally introduced into clinical practice. The first EBP was started in medicine as evidence-based medicine (EBM) and later spread to other fields such as nursing, psychology, education, and library sciences. EBP involves conscientious decision making, which is based on the best available evidence as well as preferences and patient characteristics. EBP got its reputation because of its reasoning on all procedures, medicines, and treatment thereby assuring patient safety. EBP is to enhance and promote safe medical practice, to offer guidance for diagnosing, managing, or treating clinical conditions. These EBP parameters can be used to form guidelines or advisories. The components of guideline development include review and evaluation of published scientific evidence, meta-analytical assessments of controlled clinical studies, statistical assessment of expert and practitioner opinion by formally developed surveys, and informal evaluations of opinions obtained from invited or public commentary. Sources of these evidences are based either on literature or on opinion. Literature-based sources include the randomized controlled trials (RCTs), non-RCTs, controlled observational studies, uncontrolled observational studies, retrospective studies, case series, and case reports. However opinion-based sources include views of consultants, survey opinions, invited sources, expert comments, open forum commentary, and the Internet. Because of the vast availability of studies linking professionals, EBP has been successfully incorporated into treatment services. It is now expected that the professionals must be up to date and well informed with advances and achievements in medical field to best serve their patients.
While reviewing a particular topic, it is important to have knowledge of different levels of evidence. However, it needs to be clearly stated that all levels of evidence are important. In scientific and health care field, the four levels of clinical treatment evidence mentioned in Table 54.1 are widely accepted.
| Level 1 | Level 2 | Level 3 | Level 4 |
|---|---|---|---|
| Randomized controlled trials —includes quasi-randomized processes such as alternate allocation | Non–randomized controlled trial— a prospective (preplanned) study, with predetermined eligibility criteria and outcome measures | Observational studies with controls— includes retrospective, interrupted time series (a change in trend attributable to the intervention), case-control studies, cohort studies with controls, and health services research that includes adjustment for likely confounding variables | Observational studies without controls (e.g., cohort studies without controls, case series without controls, and case studies without controls) |
To classify levels of evidence for the different categories mentioned earlier, it was necessary to derive the following table of “Classifications of Evidence.” To use these classes of evidence, one must identify the type of study and then classify it according to the following table ( Table 54.2 ).
| Class 1 | Level I studies, studies with longitudinal design with control group, studies related to basic sciences, reliability studies with >30 subjects, validity studies, professional surveys |
| Class 2 | Level II studies, studies with cross-sectional design with control groups, reliability studies with <30 subjects |
| Class 3 | Level III studies, studies with longitudinal design without control group |
| Class 4 | Level IV studies, studies with cross-sectional design without control groups |
| Class 5 | Expert opinions |
The EBM pyramid helps us understand different levels of evidence to make best health-related decisions ( Figure 54.1 ). As we ascend through the pyramid, it shows different levels, which represent the types of study design and correspond to increasing quality and reliability of the evidence.
The first level of the evidence-based pyramid is the background information or expert opinion, which is important and helpful. However, these types of evidences are influenced by many factors such as opinions, politics, or traditions. Case series/reports usually include only a few participants and case-control studies are performed in the early stage to identify variables that might predict a condition. Disadvantages of these study designs are that there are less number of participants and they are not randomized. Cohort studies include large group of participants over a period of time. These study design are difficult to blind and are not randomized. The next important level in the pyramid is the RCT. A large RCT provides a most reliable study design. In this study design, individuals are grouped into two or more groups, where one group receives the intervention and another receives no treatment or a placebo. Critically appraised topics are basically the short summaries of the best available evidence. On the top of the pyramid is systematic review. Systematic reviews and meta-analysis are considered the strongest and highest quality of evidence.
Evidence-Based Practice and Neuroanesthesia
Neuroanesthesiology is a rapidly growing superspecialty branch of medicine that has achieved remarkable growth in neuroanesthetic techniques and management. Despite achievements controversies persist. Most of the multicentric trials conducted, provide results that have little clinical significance. Most RCTs focus on surrogate end points rather than on clinical or neurologic outcomes. Some of the common issues related to the practice of neuroanesthesia are discussed in the following sections.
Target Intracranial Pressure and Cerebral Perfusion Pressure
The management strategy for treatment of raised intracranial pressure (ICP) has usually been either cerebral perfusion pressure (CPP) targeted (Rosner concept), ICP targeted or volume targeted (Lund’s concept). The “Rosner concept” states that lower CPP might precipitate intracranial hypertension, and hence advocates increasing blood pressure to augment cerebral blood flow (CBF) and CPP. Another strategy for raised ICP treatment is the ICP-targeted strategy, which focuses on aggressive reduction of ICP as the primary target. The commonest subcategory of ICP control involves a “volume-targeted” strategy (Lund concept), which is based on physiological principles for brain volume regulation and improved microcirculation. Both concepts have their own pros and cons. However, because of lack of RCTs on this topic, no approach can be considered superior to another. According to a systematic review in 2013, there is no evidence that the Lund concept is a preferable treatment option in the management of severe traumatic brain injury (TBI) and further research is needed in this field. According to the current clinical evidence, the target ICP should be maintained <20 mmHg and CPP should never exceed >70 mmHg. The target CPP should be maintained between 50 and 70 mmHg; however, critical CPP is considered to be between 50 and 60 mmHg.
Effect of Inhalational Anesthetics on Intracranial Pressure
The effect of volatile anesthetic agents on central nervous system vasculature is a depression in the cerebral metabolic rate in a dose-dependent manner. Sevoflurane cause less cerebral vasodilation compared to isoflurane or desflurane. Despite being used for more than 160 years, use of nitrous oxide in neurosurgery is still debatable among neuroanesthesiologists. The initial Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia trial brought out the query over routine use of nitrous oxide in patients undergoing major surgery. Intraoperative avoidance of nitrous oxide does not affect duration of hospital stay significantly. However, on long-term observation, the risk of myocardial infarction increases when exposed to nitrous oxide, but does not increase the risk of stroke or death. According to subgroup analysis of the General Anesthesia versus Local Anesthesia for Carotid Surgery trial, nitrous oxide use does not increase the risk of stroke, mortality, and myocardial infarction. Although nitrous oxide is a potent cerebral vasodilator, no outcome studies demonstrate its deleterious effect.
Effect of Intravenous Anesthetics on Intracranial Pressure
Total intravenous anesthesia received attention in neuroanesthesia as it avoids cerebral vasodilation. Intravenous agents such as propofol produce cerebral vasoconstriction and reduction in cerebral blood volume, CBF, and ICP secondary to decrease in cerebral metabolic rate of oxygen consumption, however, preserving cerebral autoregulation. According to the Intraoperative Hypothermia for Aneurysm Surgery trial data, administration of thiopental or etomidate does not have any significant clinically demonstrable effect on postoperative neurologic outcomes in patients undergoing temporary clipping. As per the American Heart Association/American Society of Anesthesiologists (AHA/ASA) guidelines for management of aneurysmal subarachnoid hemorrhage (SAH), at present there are insufficient data available to support their routine use, other than their use in those with high risk of prolonged temporary clipping (Class IIb, level of evidence C).
Effect of Hyperventilation and Positive End Expiratory Pressure on Intracranial Pressure
Hyperventilation has a short-term and temporary, but profound effect on CBF. It could be a life-saving measure in the treatment of acute intracranial hypertension. According to a multicentric randomized cross-over trial of hyperventilation and normoventilation in patients undergoing craniotomy for supratentorial brain tumors, intraoperative hyperventilation (PaCO 2 25 vs. 37 mmHg) was found to be associated with decreased ICP (12 vs. 16 mmHg) and 45% reduction in surgeon-assessed brain bulk. However, on the other hand, if hyperventilation is used for prolonged period, it has not been certainly shown to be beneficial to the patients. It has been observed that the patients who were hyperventilated had significantly worse outcome than those who were on normal ventilatory rate. At present, there has been no evidence to suggest that it improves clinically relevant outcomes (death or neurologic disability). Mechanical ventilation and addition of positive end expiratory pressure (PEEP) can lead to increase in ICP. However, higher level of PEEP that can be used safely without an increase in ICP is up to 15 cm H 2 O.
Effect of Hyperosmolar Therapy on Intracranial Pressure
Hyperosmolar therapy including mannitol or hypertonic saline (HS) can rapidly reduce the ICP. Raised ICP can cause global ischemia or even brain death if its value crosses 50–60 mmHg. The brain contains 80% water, so the use of hyperosmolar agents to create an osmolar gradient between the systemic circulation and brain has significant role. HS and mannitol do not cross the blood–brain barrier, hence they draw water out of the injured brain. However, in the condition wherein the blood–brain barrier is disrupted, these hyperosmolar agents will not be effective. The interstitial accumulation of mannitol is most prominent if used in continuous infusion, hence it is recommended to use mannitol as repeated boluses rather than as continuous infusion. There is no conclusive evidence that supports the role of hyperosmolar agents in saving lives or intercept disability. There is no distinct evidence at present saying that either of hyperosmolar agents, mannitol or HS are superior over another at reducing ICP. The overall outright differences in effects between these two agents have been quite less.
Effect of Various Positions on Intracranial Pressure
Various positions used during neurosurgical procedures include supine, prone, right or left lateral recumbent, park bench, Trendelenburg, and reverse Trendelenburg positions. Although prone position can be used to improve CPP in TBI, it can lead to increase in ICP due to increase in intra-abdominal pressure due to direct pressure over it. It has been observed that the supine position is associated with a lower ICP than either the prone or lateral body position with no significant differences in CPP. Lateral position without head elevation can lead to increase in ICP. Trendelenburg position can lead to increased ICP; however, reverse Trendelenburg position (30–40° head up) reduces the ICP as long as the mean arterial pressure is maintained.
Effect of Decompressive Craniectomy on Intracranial Pressure
Decompressive craniectomy (DC) is a neurosurgical procedure done for the treatment of raised ICP in patients with TBI. According to Schreckinger et al., DC is the most effective method for treatment of intracranial hypertension than cerebrospinal fluid drainage, mannitol, HS, or hyperventilation. It has been observed that DC produces overall improvement of cerebral compliance by decreasing the ICP. However, DC is also associated with many serious medical complications, intracranial infection, and also needs cranioplasty in later stage. As per the Decompressive Craniectomy in Diffuse Traumatic Brain Injury (DECRA) trial, early bifrontotemporoparietal DC was found to decrease ICP (14.4 mmHg vs. 19.1 mmHg, P < 0.001) and the length of stay in the intensive care unit (ICU) (13 days vs. 18 days, P < 0.001) but was associated with more unfavorable functional outcomes. Around 70% of patients who underwent DC died, had severe disability, or were in vegetative state compared to only 42% patients in the standard care group. Currently, there is no evidence from RCTs that supports the use of decompressive craniectomy to reduce unfavorable outcome in adults. However, in the pediatric population DC reduces the risk of unfavorable outcomes and death. Further studies are required to assess its influence on outcome.
Fluid Therapy in Neurosurgical Patients
Regarding fluid resuscitation, Saline versus Albumin Fluid Evaluation study was the first large multicenter RCT that showed no difference in 28-day mortality rate between saline and albumin groups. In patients with TBI, albumin showed 1.88 times increased risk of death at 24 months compared with normal saline (NS), possibly due to exacerbation of cerebral edema by albumin. The 2012 recommendation by the European Society of Intensive Care Medicine suggests that colloids should not be used in patients with TBI. The Crystalloid versus Hydroxyethyl Starch Trial (CHEST trial) comparing 0.9% NS fluid with 6% hydroxyethyl starch 130/0.4 in 7000 patients in the ICU, including patients with mild to moderate TBI, is expected to further give relevant information and clear the controversy of colloid versus crystalloid resuscitation in the critically ill. According to a large multicenter RCT by Bulger et al. conducted among 1282 patients with severe TBI [Glasgow coma scale (GCS) score <8] without hypovolemia, the authors observed that, compared with normal NS, HS resuscitation offered no benefit in terms of survival or better neurological outcome. Hence, the current literature does not support HS for routine use in patients with TBI; however, HS can be used as an alternative option in the treatment of patients with TBI.
Evidence for Brain Protective Strategies
There has been lot of research done to identify the neuroprotective strategies; however, no strong guidelines based on relevant clinical evidence are present. This may be due to complexity of the mechanisms in cerebral ischemia. Most anesthesiologists agree that maintaining CPP and oxygenation is the most effective neuroprotective strategy.
Hypothermia
Earlier it was believed that hypothermia offers the neuroprotective effect; however, recent large clinical trials on hypothermia failed to show improved neurologic outcomes in patients with acute brain injury. The effect of mild hypothermia (32–35 ° C) on cerebral metabolic rate is very less, compared to deep hypothermia (18–22 o C), which is neuroprotective. The National Acute Brain Injury Study: Hypothermia II trial does not support the use of hypothermia as a primary neuroprotective strategy in patients with severe TBI. Brain Trauma Foundation (BTF) guidelines 2007 provides level III evidence that prophylactic hypothermia is not significantly associated with decreased mortality. However, based on clinical data, mild hypothermia may still have beneficial effects in good-grade SAH.
Glycemic Control
Both high and low blood sugar levels are associated detrimental effect on brain along with risk of ischemia. The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation study conducted on patients in the ICU suggests that tight glycemic control [blood glucose concentration (BGC): target range 80–110 mg/dl] increases the risk of hypoglycemia as compared to conventional therapy (with BGC 180 mg/dl or less). Presence of persistent hyperglycemia after an episode of stroke increases the size of ischemic brain injury and worsens the outcome. The mortality rate decreases if the glucose levels are normalized after an acute ischemic episode. According to Bilotta et al. , intensive insulin therapy (IIT) in patients undergoing elective or emergency neurosurgery results in increased risk of iatrogenic hypoglycemia compared to conventional therapy. However, IIT resulted in short intensive care stay and low infection rate. Green et al. observed no benefit of IIT over conventional treatment on functional outcome in critically ill patients with stroke and patients with TBI.
Steroids
Corticosteroids have been widely used in patients with TBI, a leading cause of disability and death. Corticosteroids are not advised in TBI as there is no strong clinical evidence to support its benefit. According to a systematic review in Cochrane database, corticosteroids leads to increase in mortality rate and should no longer be used in patients with TBI. Also, hyperglycemia induced by corticosteroids is severely harmful.
Mean Arterial Pressure
Hypertension is commonly seen in the acute setting following stroke, raised ICP, hypoxia, pain, and stress. The AHA/ASA guidelines 2007 suggests that in patients with intracerebral hemorrhage reduction in blood pressure should only be up to 160/90 mmHg (mean arterial pressure ∼110 mmHg) (Class IIb evidence). Two clinical trials observed that low diastolic blood pressure during early ischemic stroke worsens the neurologic outcome. Antihypertensives should be the agents that are unlikely to cause inadvertent increase in ICP (e.g., labetalol, esmolol, enalapril). Precaution must be taken before administering direct vasodilators like nitroglycerine and nipride, as these drugs may cause rise in ICP and decrease in cerebral perfusion leading to deterioration of neurological condition.
Inhalational Agents
Experimental evidence confirms the neuroprotective effect of inhalational agents in both global and focal ischemia. Ischemic preconditioning by inhalational agents is an additional intrinsic mechanism of neuroprotection. This preconditioning can also be achieved when the neurons are exposed to K + channel-opening drugs that act on ATP-sensitive K + channels. These drugs do not readily cross the blood–brain barrier; however, inhalational agents that easily enter into brain precondition various tissues. According to Bantel et al., xenon generates preconditioning mechanism by activation of ATP-sensitive K + channels; however, the preconditioning property of halogenated volatile agents cannot be explained by their effect on K + ATP channel. Hence, xenon closely mimics the intrinsic mechanism of preconditioning and is a viable neuroprotective inhalational agent.
Intravenous Agent
Barbiturates also have neuroprotective ability; however, mixed results have been published and its perioperative clinical efficacy is controversial. Propofol attenuates the level of S100beta (marker of brain injury) and improves neurological outcome. The neuroprotective effect of propofol results from activation of γ-aminobutyric acid receptor and modulation of excitatory amino acid transmitter system. Propofol protects brain cells from oxidative stress and also suppress apoptosis. According to Schifilliti et al., after conducting a systematic search, data indicate that anesthetic drugs such as barbiturates, propofol, xenon, and most volatile anesthetics (halothane, isoflurane, desflurane, sevoflurane) have neuroprotective effects that protect the brain tissue from adverse events, such as ischemia, apoptosis, degeneration, or inflammation. At present, no data supports the selection of one anesthetic agent over the others. Furthermore, it is important to highlight that many studies were conducted in animals or in vitro, hence the conclusion that these studies cannot be directly applied to the clinical setting. Further large randomized trials or systematic reviews are required on this topic.
Magnesium (Mg 2+ )
Magnesium has many functions, but has also been suggested to have neuroprotective property. There are various mechanisms that helps in rendering its neuroprotective effect, namely, they act as an N-methyl- d -aspartate receptor antagonist, inhibit the release of excitatory neurotransmitter (glutamate), and act as an endogenous calcium channel antagonist. Magnesium has found to reduce the risk of delayed cerebral ischemia in patients with SAH because of its direct vasodilatory effect. Magnesium and minocycline is a potent combination having a positive therapeutic role in management of cerebral ischemia through its antioxidative, antiinflammatory, or antiapoptotic features. The fact that magnesium sulfate has a neuroprotective role in antenatal therapy when given to women at risk of preterm birth for the preterm fetus is now established.
Dexmedetomidine
There has been increasing evidence for dexmedetomidine in neuroprotection, cardioprotection, and renoprotection. It has been observed that in combination with propofol, dexmedetomidine exerts a stronger neuroprotection against ischemia-reperfusion (I/R) injury when compared with propofol or dexmedetomidine alone. The ketamine and dexmedetomidine combination is increasingly used in pediatric patients. According to a study by Duan et al., on neonatal rats, ketamine cause neuroapoptosis and impaired brain functions, which can be effectively attenuated by dexmedetomidine. In an in vitro model of TBI, dexmedetomidine had shown a significant neuroprotective effect. Activation of extracellular signal-regulated kinases might be involved in mediating the neuroprotective effect of dexmedetomidine.
There are no formal guidelines present regarding intraoperative neuroprotection. Most of the clinical evidences are weak due to lack of large RCTs. The recommendations mainly consist of avoidance of deleterious interventions rather than beneficial measures.
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