HOW TO MAKE MOST OF KEYWORDS 1994 These keywords don't substitute a regular textbook, but are merely a supplementary text for you to browse through once you have read the standard text. These keywords have been prepared with that vision in mind. The ABA / ASA provides the key words under several sections. However to facilitate your reading the keywords have been reorganized according to the subject matter. It is thought that after reading a standard text you will go through the keywords related to the text. Consider the various possible questions that may arise from the both the text and the keywords. Don't just be satisfied reading the keywords alone. If you can get past years keywords or previous years examination papers it will be a great help. Concentrate on those keywords that have been written by the current third and the fourth year. Since this group got to write the low scoring key words. The keywords have been provided in the binder so that next year's keywords can be filed along with the current ones and for you to add supplementary information. Hopefully we will not have to do all the keywords next year as a fairly high percentage of the keywords are repeated. One side printing has been done to enable you to make notes etc..It is also hoped you will find sections on 'Useful Information' and 'Recent Reviews' helpful. Don't forget to read the 'One Last Word'. S. Joshi, FFARCSI Visiting Assistant Professor *********************************************************************** EFFECTS OF LIDOCAINE ON THE EEG Intravenous lidocaine produces a reproducible sequence of electrical changes including cortical slow activity and changes in amygdaloid nuclear complex. A subconvulsive dose of lidocaine causes one of the following changes in the amygdala 1.Rhythmic high voltage discharge 2.Similar high voltage discharge with a brief high frequency burst superimposed on one of the limbs 3.A rhythmic spindle burst With a higher subconvulsive dose of lidocaine, #1 & #2 preceed #3. After a convulsive dose of lidocaine, a focal discharge, incremental in voltage, consisting of rhythmic spike-like potentials, develops in the basal amygdala. Arrested movement and staring occurs during electrical discharge. The amygdala discharge culminates in high voltage generalized seizure activity in all leads. Following termination of generalized activity, the changes are similar to those seen during a subconvulsive dose. The electrical seizure does not always begin in the amygdala. When large convulsive doses are given the discharge appears almost simultaneously on the surface and in the depths. ---------------------------------------------------------------------- REFERENCE: deJong RH, Robles R, Corbin RW: Central Actions of Lidocaine - Synaptic Transmissions. Anesthesiology 30:19, 1969. *********************************************************************** TOXICITY OF BUPIVICAINE CNS Cerebral Cortex Stimulation - restlessness, nervousness, incoherent, speech, metallic taste, dizziness, blurred vision, tremors, convulsions Depression - unconsciousness Medulla Stimulation - Increased blood pressure, heart and respiratory rate, nausea & vomiting Depression - Hypotension, apnea, asystole Cardiovascular * Precipitous hypotension * Cardiac dysrhythmias - PVC's, wide QRS, V tach, SVT, ST-T changes, A-V block * Dose related decrease in contractility & rate of cardiac electrical potentials * Overdose results in refractory cardiac arrest so now 0.75% is available for spinal but not epidural anesthesia. * Pregnancy increases sensitivity to cardiotoxic effects. * Persistent depression of maximal depolarization rate of the cardiac action potential (Vmax) occurs because the dissociation of the highly lipid soluble bupivacaine from the sodium channel receptor sites is slow. * Tachycardia can enhance frequency dependent blockade of cardiac sodium channels by bupivacaine from the sodium channel receptor sites is slow. * In dogs, Bretylium 20 mg/kg IV reverses bupivacaine induced cardiac depression & elevates the threshold for VT. * Bupivacaine is relatively more cardiotoxic than predicted from local anesthetic potency because of its electrophysiologic effects. -------------------------------------------------------------------- REFERENCE: Stoelting, Robert K. Pharmacology & Physiology of Anesthetic Practice, 2nd. Edition ******************************************************************** ETOMIDATE AND ADRENOCORTICAL SUPPRESSION Etomidate causes adrenocortical suppression by producing a dose dependent inhibition of the conversion of cholesterol to cortisol. The specific enzyme inhibited by etomidate appears to be 11-beta- hydroxylase as evidenced by the accumulation of 11- deoxycorticosterone. The enzyme inhibition lasts for 4 to 8 hours after an induction dose of etomidate. Disadvantage - may contribute to a "stress-free" anesthetic. In at least one report it was not possible to demonstrate a difference in the plasma concentrations of cortisol, corticosterone or adrenocorticotrophic hormone in patients receiving a single dose of etomidate. ---------------------------------------------------------------------- REFERENCE: Stoelting, Robert K. Pharmacology & Physiology of Anesthetic Prac ********************************************************************** TOXICITY OF ATROPINE Scopolamine, and to a lesser extent atropine, can enter the CNS and produce symptoms characterized as the central anticholinergic syndrome. Symptoms - restlessness, hallucinations, somnolence, unconsciousness. This is due to blockade of muscarinic cholinergic receptors in the CNS. Glycopyrrolate does not easily cross the BBB. Arousal in the first 30 minutes following cessation of anesthesia is delayed following administration of atropine-neostigmine mixture but not glycopyrrolate-neostigmine mixture. Physostigmine, 15 - 60 æg/kg is the treatment for central anticholinergic syndrome. Side Effects * Increased heart rate - atropine > glycopyrrolate or scopolamine. * Lowers GE sphincter tone - theoretical increase in risk of aspiration. * Closed angle glaucoma - peripheral iris contacts posterior corneal surface causing obstruction of aqueous outflow. Patients with narrow angle between posterior cornea and iris are more susceptible & mydriasis can thicken peripheral iris to block outflow. * inhibits sweating and increases temperature. -------------------------------------------------------------------- REFERENCE: Stoelting, Robert K. Pharmacology & Physiology of Anesthetic Practice. 2nd. Edition ********************************************************************* PHARMACOKINETICS OF FENTANYL Fentanyl * Rapid onset (30 sec) high lipid solubility crosses BBB quickly. * Short duration of action redistribution to fat, muscle, lung. * When multiple doses are given, inactive tissue sites become saturated and may cause prolonged duration of analgesia & respiratory depression (at the end of the case). * Metabolism - dealkylated, hydroxylated, amide hydrolyzed to inactive metabolites norfentanyl & desproprionylnorfentanyl that are excreted in bile & urine. (85% appears in bile & feces over 72 hrs) (8% unchanged drug in urine). * Elimination half-time - 185-219 min (high because of large volume of distribution due to its greater lipid solubility). * Fentanyl's Vd, clearance and T« are similar to MSO4. * Fentanyl's penetration of BBB is faster. * After a prolonged infusion, the rate of decrease in concentration at the site of action is slower than sufenta or alfenta. ------------------------------------------------------------------- REFERENCE: Stoelting, Robert K. Pharmacology & Physiology of Anesthetic Practice. 2nd. Edition. ****************************************************************** PHARMACOKINETICS OF ALFENTANIL Alfentanil 1) Volume of distribution is 4-6 times smaller than fentanyl (lower lipid solubility & greater lipid binding). 2. Rapid penetration of BBB because of high degree of nonionization (90%) at physiologic pH. #1 & #2 more rapid onset. * Elimination half-time - 70-98 min. * Clearance depends more on hepatic blood flow and is more predictable. * Cirrhosis but not cholestatic disease prolongs elimination half- time. Not affected by kidney disease. * Small Vd decreases effect of redistribution. * E« is short * Metabolism - N-dealkylation to form noralfentanil & conjugation with glucuronic acid. * <0.5% excreted unchanged in urine. * 96% eliminated from plasma within 60 min following injection. * Erythromycin can inhibit metabolism & prolong effects. * Potency is 1/5 to 1/8 of fentanyl. * Alfentanil is the drug of choice for rapid transient peak effect after a bolus. * Alfentanil is the drug of choice for infusion if the case is to last >6-8 hrs & you desire a rapid decrease in concentration at the effector site at the end of the case. pK Protein Vd Clearance Elimination Binding% L/kg Ml/kg/min T« min Alfentanil 6.5 89-92 0.5-1 5-7.9 70-98 Fentanyl 8.43 79-87 3.2-5.9 11-21 185-219 Sufentanil 8.01 92.5 2.86 13 148-164 ---------------------------------------------------------------------- REFERENCE: Stoelting, Robert K. Pharmacology & Physiology of Anesthesia Practice. 2nd. Edition. ********************************************************************** INHALATION INDUCTION IN INFANTS Inhalation induction is very common and useful in infants because of difficulty getting IV access in an awake child. However, IV induction is preferred if venous cannula is already in place. A combination of oxygen, nitrous oxide and halothane are used. Enflurane and isoflurane are avoided because of their ethereal pungicity. Halothane should be slowly added to prevent bronchial irritation and possibly laryngospasm. A constant monotonous voice can calm an upset child. After induction, you can switch to isoflurane which has less cardio vascular depressant effect than halothane. In general inhalation induction is quicker in children because of a lower FRC per body weight and a higher percent of vessel risk groups (ie brain) per body weight. Complications of inhalation induction include breath-holding, laryngospasm, and stomach distention. There is a higher incidence of bradycardia, hypotension, and cardiac arrest during inhalation induction in children compared to adults. A single breath halothane technique is rarely necessary. The breathing system is primed with 5% halothane and the face mask tightly applied. A single vital capacity breath taken by the patient would rapidly induce anesthesia. Be aware of cardiac shunts. Right to left shunt slower uptake Left to right shunt faster uptake Once induction is completed, the infant can be intubated as usual with succinylcholine. Atropine should be used to prevent succinylcholine induced bradycardia (infants have rate-dependent cardiac output). Recent concerns about the use of succnylcholine have led to the more frequent use of other competitive blocking drugs. Inhalation induction is often necessary in patients with significant airway obstruction, e.g. epiglottitis. Such induction is frequently slow due to decreased alveolar ventilation, increased cardiac output, avoidance of nitrous oxide and fever ( increases the MAC and cardiac output ). Anesthetic requirements vary with age. Generally, the MAC is higher in children than in adults. In infants the MAC is smaller than children but quickly rises until age one. -------------------------------------------------------------------- REFERENCE: Clinical Anesthesia - Barash p. 1338. ******************************************************************** PRE-ANESTHETIC EVALUATION OF LIVER DISEASE Liver has numerous functions: 1. Production of albumin, clotting factors. 2. Metabolism of glucose, fats, proteins, urea, bile. 3. Excretion of bile. 4. Detoxification of exogenous and endogenous materials. Things to Consider: 1. Type of surgery planned. 2. Past medical history. a) co-existing diseases b) severity of present disease c) history of bleeding d) cause of liver disease e) history of jaundice f) history of encephalopathy 3. Physical exam - how sick is your patient? a) Generally - how is the nutritional status b) CNS - signs of encephalopathy, alcohol withdrawal c) CV - cardiomyopathy? Irritable myocardium from bile deposition? d) GI - bleeding, ascites e) Respiratory - effusions, pulmonary edema f) Renal - volume status, renal fxn 4. Testing Blood - hemoglobin, platelet count, electrolytes, prothrombin tissue, S.P.E., A.B.G. CXR, EKG Classification Schemes 1963 - Childs Bilirubin (mg/dl) <2 2-3 >3 Albumin (g/dl) >3.5 3-3.5 <3.0 Ascites None Controlled Not controlled Neuro status None Minimal Coma Nutrition Excellent Good Poor Class A B C Mortality 5% 18% 68% 1973 - Pugh Encephalopathy (occurrences) None 1-2 >3 Bilirubin (mg/dl) <2.5 2.5-4 >4 Albumin (g.dl) 3-5 2.8-3 <2.8 Prothrombin (time seconds prolonged) 1-4 4-6 >6 Grade 1 2 3 Four Main Causes of Death 1. Massive bleeding 2. Sepsis 3. Hepatorenal syndrome (multi-organ failure) 4. Encephalopathy ------------------------------------------------------------------------------- References: 1. Clinical Anesthesia, 2nd Ed., Barash 2. Anesthesia and Coexisting Disease, 2nd Ed., Stoelting 3. Pathologic Basis of Disease, 4th Ed., Robbins ****************************************************************************** HYPOXEMIA IN LIVER DISEASE 1. Increased shunting across the lungs, which is not responsive to increased oxygen. Presumably, due to elevated levels of glucagon and V.I.P. which dilate pulmonary vascular beds. 2. V/Q mismatch secondary to increased closing volumes. (This is due to ascites). This leads to gas trapping in the lower lung zones. 3. Pleural effusions - yield mechanical difficulties with respiration. 4. Right shift in the oxygen - hemoglobin curve due to increased levels of 2,3 DPG in the RBCs. -------------------------------------------------------------------------- References: 1. Clinical Anesthesia, 2nd Ed, Barash 2. Anesthesia and Coexisting Disease, 2nd Ed., Stoelting MUSCLE RELAXANTS AND LIVER DISEASE Depolarizers Succinylcholine - severe liver dysfunction may reduce plasma cholinesterase activity and prolong its effect. Non-Depolarizers 1. Atracurium - relaxant of choice - little change in volume of distribution, little effect on metabolism. 2. Vecuronium - No significant increase in the volume of distribution, no increase in elimination half-life for cirrhotics until dose is greater than 0.15 mg/kg. Patients with obstructive biliary problems may manifest a prolonged elimination due to its high biliary clearance. 3. Pancuronium - there is a two-fold increase in both volume of distribution and the elimination half-time. 4. dTc, gallamine and metocurine - do not depend on hepatic metabolism. ------------------------------------------------------------------------------- References: 1. Pharmacology and Physiology, 2nd Ed., Stoelting. 2. Clinical Anesthesia, 2nd Ed., Barash. 3. Anesthesia and Coexisting Disease, 2nd. Ed., Stoelting. ******************************************************************************* LIVER DISEASE: INDUCTION OF ANESTHESIA All i.v. agents have been used successfully for induction, however, there are several things to consider when choosing an agent. 1. Does the liver disease prolong the effects of the induction agent? The texts say that it is unlikely a single dose of drug used for induction will have a prolonged effect. This is because the termination of its effect is due to redistribution and not metabolism. 2. How will hypoproteinemia effect induction? Thiopental, midazolam and propofol are moderately to highly bound to plasma proteins, and there could be a net increase in the potency of a drug due to more free drug available in the hypoproteinemic patients plasma. Ketamine is not highly protein bound, and is not affected by decrease plasma protein levels. 3. How is the volume of distribution changed? Most moderate to severe liver disease patients have an increase in total body water. This is because there is a hyperaldosteronemic state which manifests in decreased water elimination. For most of the drugs we use, this yields an increase in the volume of distribution for the drug being used. This would essentially dilute the drug rendering it less potent, and a higher dose needed to achieve the desire effect. 4. Do the drugs damage the liver? Etomidate, propofol, midazolam, and thiopental are all safe to use, but there is some evidence to suggest Ketamine can cause hepatic artery constriction, and hepatocyte damage. ------------------------------------------------------------------------------ References: 1. Clinical Anesthesia, 2nd Ed., Barash 2. Pharmacology and Physiology, 2nd Ed., Stoelting 3. Anesthesia and Coexisting Disease, 2nd Ed., Stoelting **************************************************************************** POST TRANSFUSION HEPATITIS Overall incidence of risk of hepatitis from transfusion despite testing and screening for hepatitis B and C is 0.03% per unit. HBV HCV Specific incidence 10% 90% Chronic hepatitis 5-10% 50% Chronic persistent hepatitis 2% 35% Chronic active hepatitis 307% 15% ------------------------------------------------------------------------------ References: 1. Circular of Information, American Red Cross, March, 1989 2. Overview of Hepatitis C, Laboratory Medicine, Vol 23, No. 12, December 1992. 3. Hepatitis C: The Newest Old Virus, Joy L. Friday, A.S.C.P., Spring, 1991. Teleconference Series. 4. Munoz, etal., New England Journal of Medicine 327: 419-421, 1992 ****************************************************************************** RELAXANTS IN BURN PATIENTS 1. Decreased affinity of acetylcholine and nondepolarizers for cholinergic receptors. This yields a hypersensitivity to depolarizers and resistance to nondepolarizers. This effect is proportional to the burn size, and is greatest from about day 5-120. ---------------------------------------------------------------------------- References: 1. Pharmacology and Physiology, 2nd Ed., Stoelting 2. Clinical Anesthesia, 2nd Ed., Barash 3. Anesthesia, Miller **************************************************************************** INTRAOPERATIVE HYPOTENSION AND LIVER DISEASE Hepatic Blood Supply: Hepatic Artery Portal Vein %flow 30 70 % Oxygen supply 45-50 50-55 Pressures Blood pressure Control of Flow: 1. Hepatic artery - controlled primarily by local and intrinsic mechanisms in the arterioles. 2. Portal flow - controlled by arterioles in the preportal splanchnic organs. 3. Reciprocity of flow - a decreased flow through either the hepatic artery or portal vein will lead to a concomitant increase in flow through the other in order to keep total hepatic flow constant. Anesthetics and Their Effects on Hepatic Flow. 1. Inhalation agents. Halothane > Enflurane > Forane Greater reduction lesser reduction The effects of halothane are dramatic, estimates at 1 MAC to be a 30% decrease in flow. 2. IV agents a) Thiopental, propofol, midazolam, and etomidate have little effect on blood flow to the liver. b) Ketamine does tend to reduce hepatic blood flow. Hypotension Effects on the Liver: Centrilobular necrosis. ---------------------------------------------------------------------------- References: 1. Clinical Anesthesia, 2nd, Ed., Barash 2. Anesthesia and Coexisting Disease, 2nd Ed., Stoelting 3. Pathological Physiology for Anesthesiology, Smith **************************************************************************** THE CONTROL OF BREATHING - FURTHER READING If you want to probe this subject further be careful this is one of the most complex areas to explore. There are major contradictions between authors, may be due to their experimental design. The research too, seems to be scattered in time and location. But like any other complex hypothesis it is interesting to read provide you have the time and the ability to grasp the facts. Basic Text: Wylie : A Practice of Anaesthesia,VI Edition 1983, Chapter 2 page 32 : Easily the best and the most concise text strongly recommended, the only problem is that it is too old but it will still do for both understanding and the boards. Scurr: Scientific Foundations of Anaesthesia : III edition 1990 Chapter Page ,: This information is concise but too abridged and tragically incomplete just gives some idea as to how the respiratory system control is organized and little beyond that. If you want to understand the basic organization of the respiratory control read this, will not suffice for the boards. Guyton : Text Book of Physiology : Chapter 42 : The regulation of respiration, Page 504 : Must read chapter in basic physiology. West : Respiratory physiology Chapter 8 : Control of ventilation how gas exchange is regulated page 116 , a short simple chapter. Best one for understanding the subject. Does not give effects of anesthesia. Nunn : General Anaesthesia, 1990 : Effect of anaesthesia on breathing Chapter 14, Page 185. The chapter has a short concise section on the control of breathing, page 188-190, excellent for exam, insufficient for understanding. Barash : Clinical Anesthesia II Edition 1992 Chapter 17 Inhaled Anesthesia : Page 446 contains some information on the effects of inhaled anesthetics on the respiratory drive, namely chemical, the paper quoted still are from Eger 1981, this chapter is no different from the one mentioned above. Miller : Anesthesia : Chapter 15 deals with Respiratory Physiology and Respiratory Function During Anesthesia, Page 505: This chapter by Benumof merely glances on respiratory control mechanisms on page 532, thoroughly incomplete. RECENT REVIEWS: Jennings D B : Breathing for protein functions and H+ homeostasis . 33 References : Respiratory Physiology 1993 July; 93 (1): 1 - 12. Patterson D J : Potassium and Ventilation during exercise. 88 References. J Appl Physiol 1992 Mar; 72 (3) : 811 - 20. Fleming P J et al : Interactions between thermoregulation and the control of respiration in infants: possible relationship to sudden infant death : Acta Paediatr Suppl 1993 Jun; 82 Suppl 389 : 57 -9. Scano G et al : Control of breathing in patients with neuromuscular diseases. Monaldi Arch Chest Dis 1993; 48 (1) : 87 -91. Tardif C et al: Control of breathing in chest wall diseases. 33 References. Monaldi Arch Chest Dis 1993; 48 (1): 83 -86. Clark A et al: The mechanisms underlying the increased ventilatory response to exercise in chronic stable heart failure. Eur Heart J 1992 Dec ; 13 (12): 1698 - 708. Elkus R et al : Respiratory Physiology in pregnancy. 82 Refs Clin Chest Medicine 1992 Dec 13 (4) 555 - 65. This article also deals with mechanics of respiration during pregnancy. Recommended. Cummin A R et al : Ventilatory response to carbon dioxide below normal control point in conscious normoxic humans. Euro Resp J 1992 May (5): 512 - 6. Valimaki I et al: Adaptation of cardio respiratory control in neonates. J Perinat Med 1991; 19 Supple 1 : 74 - 79. Lagercrantz H et al : Functional role of substance P for respiratory control during development. Ann N Y Acad Sci 1991; 632 : 48 -52. Mador M J : Respiratory Muscle Fatigue and Breathing pattern. Chest 1991 Nov; 100 (5): 1430 - 5. Adamson S L : Regulation of breathing at birth. J Dev Physiol 1991 Jan 15 (1) : 45 - 52. Milsom W K : Intermittent breathing in vertebrates. Annu Rev Physiol 1991; 53 : 87 -105. Finally, if you really want to get down to the state of art levels in this subject the Handbook of Physiology Section 3,volume II part 1 and 2 are virtually devoted to Respiratory Regulation containing 908 pages of dense text. Even that now is a bit mouldy being a 1986 publication. *********************************************************************** BASICS OF OBSTETRIC ANESTHESIA Physiological changes : Cardiovascular system Respiratory system CNS Renal Hepatic Gastro Intestinal Physiology of Uteroplacental Circulation Fetal Uptake and Distribution of Drugs Maternal Medication During Labor : Anxiolytics Narcotics Ketamine The Progress of Labor Regional Anesthesia of Labor and Delivery Inhalation anesthesia for vaginal delivery Anesthesia for Cesarian Section Abnormal Presentations and Multiple Births Pregnancy and heart disease Toxemia of pregnancy Hemorrhage in the parturient - SHOCK IN OBSTETRIC PATIENT Amniotic fluid embolism Anesthesia for Non obstetric surgery during pregnancy Diagnosis and management of fetal distress Evaluation of the neonate Post partum tubal ligation. GENERAL ANESTHESIA FOR CESARIAN SECTION : CONSIDERATIONS : 1. 130 years of life at stake. 2. Maternal Mortality as an indicator of quality of health care. Anesthetic Considerations: 1. Risk of aspiration 2. Fetal depression 3. Maternal Hypoxemia 4. Failed intubation 5. hypotension 6. Awareness 7. Uterine relaxation 8. Hemorrhage ASPIRATION : Solid Vs Liquid Aspiration : Atelectasis vs pneumonitis. Mandelson syndrome : Curtis L. Mandelson, Cornell Univ, 1946, Am J Obs Gyn. Pregnancy as a risk of aspiration: 1. Delayed GET : Gastric Hypotonia Altered Position of the stomach Increased intra abdominal pressure 2. Progressive increase in the gastric secretion during pregnancy. Critical pH : < 2.5 Pepsin activity: < 4.5 Rebound Secretions : > 6.0 Critical Volume : > 0.4 ml/kg Recommended target : pH > 2.5, Volume < 25 ml Pathology of Pulmonary Acid Aspiration: 0 - 4 Hours Bronchial Epithelium Degenerates Thrombosis of the pulmonary artery Necrosis of type I pneumocytes Protein rich hemorrhagic fluid Polymorphic infiltration Degeneration of Type II cells in 4 hours 24 - 36 Hours Bronchial mucosa sloughs off > 72 Hours Regeneration of bronchial epithelium Bronchiolitis Obliterans : Atypical regeneration of Bronchial Epithelium. Proliferation of type II cells 2 -3 wks Fibrosis and scarring. ****************************************************************************** CEREBRAL BLOOD FLOWS AFTER INJURY I. Introduction : Incidence of ischemia in Traumatic brain injury. Incidence of ischemia during treatment of head injury. Vulnerability of traumatic tissue to ischemia. Inability to abort on going ischemic damage despite restoration of systemic oxygenation. II. Determination of cerebral blood flows in clinical TBI: Kety and Schmdit's Method: assumptions and technique advantages and disadvantages clinical use - Robertson studies Radioactive gas injection methods : Ficks Principle One Dimensional Analysis Two dimensional Analysis clinical studies: Oberist 1984 Muizalaar 1992 Single Photon Emission Analysis: The Principle Single Photon Emission CT Scanning,the three dimensional analysis. clinical Studies : Bouma et al SPECT 99mTc HMPAO Principle and limitations Ballock study : the ischemic halo Transcranial doppler : Principle and applications Incidence of vasospasm in head injury Chan study : time course of cerebral hyperemia Gomez study : MFV and ICP, CO2 and pH reactivity Thermal Diffusion : Principle , advantages and disadvantages Correlation with other methods Jugular Venous Saturation AVjDO2 Fiberoptic assessment. Cerebral extraction of O2 and its significance Cerebral Angiography: incidence of spasm III. Regulation of CBF in health: Anatomy : The cerebral arteries : peculiarities, the BBB Physiology Regulation of cerebral circulation Significance of the circle of Willis Cerebral capillaries A V shunts and Veins. IV. Pathological Changes in head Injury Pressure auto regulation: Incidence and extent of loss Cerebro Vascular Reactivity The effects of the loss of pressure autoregulation. Altered Metabolic Regulation: The significance of monitoring AVjDO2 Cerebral Hemodynamic Reserve Mechanism of loss of pressure autoregulation Effect of Viscosity on Autoregulation: Effect of hemodilution on blood viscosity. CO2 Reactivity in head injury Extent of loss of CO2 reactivity. N acetyl cysteine and CO2 reactivity. Blood Volume Responsivity Blood Brain Barrier in Head Injury V Effect of blood volume on intracranial compliance. VI. Therapeutic Implications: Reduction of CMRO2 : Moderate Hypothermia Increasing Cerebral Blood Flows: Increasing Cerebral Perfusion Pressure Use of Prostaglandin inhibitors Use of CCB drugs Effect of positioning on head injury. Mannitol in head injury Hazards of hyperventilation VII Summary **************************************************************************** CEREBRAL BLOOD FLOWS AFTER INJURY There is little doubt that ischemia plays an important role in secondary brain injury (), the universal occurrence of ischemia in clinical neurotrauma, however, remains inconclusive ( ). Graham et al based on autopsy findings quote an incidence of over 90%, that incidence has changed little in the last 20 years (). Other studies indicate approximately 30% incidence of ischemia after neurotrauma (). There is evidence that the evidence of ischemia is influenced by the age (), the clinical severity of injury () and the time after injury (). This is in contrast to other papers that suggest cerebral hyperemia rather than cerebral ischemia occurs in early neurotrauma (). The problem has arisen because of logistic and technical difficulties in early assessment of cerebral blood flows, at a time when urgent therapeutic interventions take precedence over subtle time consuming diagnostic tests (). Besides this several authors have been inconsistent in what they describe as 'the early period', which frequently ranges from hours to days and weeks (). Even today there are few clinical studies that have evaluated cerebral blood flows in the first twelve hours of neurotrauma (). The catastrophic metabolic cascade that is triggered by an ischemic insult in cerebral tissue is well recognized (). There is experimental evidence that the traumatized brain is highly sensitive to ischemic injury(). Further, experimental evidence also indicates that correction of systemic oxygenation may not be able to prevent ongoing ischemic cerebral damage (). Today, there are a number of options in the treatment of cerebral vasospasm and there is promising therapy capable of interrupting the aftermath of ischemic injuries (). Thus the conclusive demonstration of early cerebral ischemia could provide the missing therapeutic link between the alterations in the cerebral circulation and the outcome of head injury(). It has been suggested, that the singular emphasis on restoration of intracranial pressure may be the reason, why significant qualitative improvements in neurological outcome have not been achieved despite two decades of neurosurgical intensive care (). This review deals with methods of assessing cerebral blood flow and the results obtained by the various methods in early neurotrauma. We will then look at the normal cerebral circulation and pathophysiology of cerebral circulation in head injury. The critical effect of cerebral blood volume on the intracranial compliance. Finally, we will deal with the therapeutic options aimed to modulate cerebral circulation in early clinical neurotrauma. *************************************************************************** DETERMINING CEREBRAL BLOOD FLOWS IN EARLY CLINICAL NEUROTRAUMA: The cerebral blood flows in early clinical neurotrauma can be assessed by several methods: Kety and Schmidt's N2O inhalation method, intra carotid 133Xe injection with external monitoring, 133Xe inhalation with computed tomography,dynamic CT Scanning, thermal diffusion and 99m Tc HMPAO SPECT have all been used. Indirect measurements of cerebral blood flows have also emerged from the Jugular Venous Bulb saturation and Transcranial Doppler. Cerebral angiography with or without digital substraction has also helped demonstrate cerebral vasospasm after head trauma. Kety and Schmidt's Method : The classical determination of CBF by Kety and Schmidt method (1945). The method remains the gold standard against which other CBF determination techniques are compared (). Traditionally it requires inhalation of N2O till equilibrium is achieved, and under these circumstances it could be assumed that the concentration of N2O in the brain was equal to that of the venous blood, further the amount of the tracer that was dissolved in the brain was proportional to it's partition coefficient. This method however also assumes that the cerebral blood flow is in steady state, there is uniform mixing of the tracer, the tracer is not metabolized, and no previous tracer is present, while the partition coefficient of the tracer has to be known. In acute trauma this method has been used in several centers. It however requires at least 10 minutes for equilibrium. The mild vasodilator properties of nitrous oxide can potentially alter the cerebrovascular resistance and the increase the ICP (). The method gives a global but not regional cerebral blood flows and may therefore mask regional ischemia (). However, it can easily be combined with metabolic measurements to yield CMRO2 and other metabolic indices. Robertson et al have used this method serially in the first ten days of neurotrauma in 184 patients. Their finding suggest that when the effect of CBF on neurological outcome is adjusted for age, initial GCS, hemoglobin concentration, cerebral perfusion pressure,and CMRO2, a reduced cerebral blood flow is significantly associated with a poor neurological outcome ( Table 1). Radioactive gas injection technique : 85Kr and 133Xe have been injected intra arterial to determine the cerebral blood flows. These gases have low solubility and rapidly equilibrate with the cerebral tissue. They are also completely eliminated through the lungs consequently it can be assumed that the arterial concentrations of these is zero after intra arterial injection is completed. This simplifies the Fick's Equation. The decay of the radioactivity is a function of cerebral blood flow and the half life of the isotope. In the so called one dimensional determination of CBF the global cerebral blood flows are assessed by determining the rate of wash off of radioactivity in the Jugular Venous bulb blood sample. In the two dimensional determination of the CBF the use of a gamma emitting isotope permits the use extra cranial detector. The number and placement of the detectors may vary so as to focus on an area of interest.This number may vary from as little as 10 ()to as many as 253 (). Thus the regional blood flows can thus be determined. Also the rate of decay of radio activity follows a biexponential curve, due to different cerebral blood flows to gray and the white matter. The problem with two dimensional determination is the spatial resolution since there is considerable cross talk between the two hemispheres (). In order to avoid complications of intra arterial techniques inhalation and intravenous injection techniques have been used but these require different strategies for clearance curve analysis(). The classic study by Oberist 1984 ().Muizelaar et al used two dimensional CBF determination using the 133Xe inhalation method in 32 pediatric severe closed head injuries. His group found that statistically insignificant reduction in the CBF, parallel to low GCS, in the first 24 hours of injury. However there was evidence of cerebral hyperemia after 24 hours in all except the severest cases. Based on the reduction of AVjDO2 there also seemed to be an uncoupling of the CMRO2 and CBF (). Single Photon Emission Analysis: Certain isotopes as 133Xe , 131I, 99mTe emit only one photon per disintegration. These isotopes have been used in SPECT, ie Single Photon Emission Computed Tomography. The measurement requires inhalation of the marker, and for approximately 3 one minute periods after inhalation a series of four tomographic images are taken. It gives the CBF in three slices of the brain with a resolution of 1.5 -1.7 cm in the plane and 2 cm axially. 133Xe CT was used for the determination of CBF within 50 minutes to 8.5 after injury by Bouma et al in 35 severe head injuries (). They found a 31.4% incidence of global ischemia. Normal or high CBF were not associated with adverse outcome. Diffuse cerebral injures were associated with reduced CBF and in over 50% with evidence of ischemia. While with intra cranial hematomas there seemed to be focal ischemia. Ischemia was associated with early mortality , p < .02. Another application of SPECT technology has been the development of SPECT tracers, such as 99m Tc - D- L- hexamethylene propyleneamine ( 99mTc HMPAO ). These tracers are sequestered in the brain tissue within first few minutes of intravenous injection and are retained for the next 5 -6 hours. These are not reliable indicators of CBF but provide a clear picture of CBF distribution. Bullock et al() used 99m Tc HMPAO mapping to study early post traumatic CBF distribution in patients with focal brain injuries. These scans were performed up to 21 days of injury. His group tried to correlate the CBF distribution with structural damage. Their group could not determine the CBF but did show a consistent zone of ischemia around mass lesions , such as contusions and hematomas, that were > 1.5 cm. This zone of reduced CBF persisted for weeks to months after injury. They attributed this to the swelling of the astrocytes rather than vasospasm. They also demonstrated focal hyperemia in 42% of the patients. This hyperemia was seen in the normal tissues adjacent to the focal lesions. Dynamic CT Scans: Yoshino et al (1985) used dynamic CT Scanning to semi qualitatively evaluated CBF within 2 hours of injury. They detected severe ischemia in 17 of the 25 fatalities in their series. This study raised two pertinent questions. First, was this ischemia reversible? The study did not follow up the cases with subsequent blood flow measurements. The second , how reliable is dynamic CT Scanning as an indicator of cerebral ischemia? Since there are no correlation studies on the diagnostic reliability of the technique. Transcranial Doppler : The use of transcranial ultrasonography has been used to assess the cerebral blood flow after head injury. The mean flow velocity (MFV) in the intracranial vessels can be non invasively be determined using this technique. However the data used in isolation yields little information. The velocity of blood in the vessel can be altered both by the change in the flow or the alteration in the cross sectional diameter(). Thus the information generated has to be combined with other measurements such as AVjDO2, CPP, etc or radiological investigations like cerebral angiography to document cerebral vasospasm. Chan et al () used this technique in 121 patients, fifty of whom had severe head injuries. Seventeen of these fifty patients had MFV exceeding 100 cm/sec this was frequently associated with cerebral hyperemia, defined as AVjDO2 < 4. Patients with severe head injuries the increase in the MFV was seen on the second day and the median duration of effect lasted for four days. In contrast an earlier study by Gomez et al ()observed MFV in nine moderate to severe head injuries. Eight of the patients in this series had MFV exceeding 110 cm/sec. These velocities were determined within 2 weeks of injury and the mean duration of increased MFV was 11 days ( range 3 -24 days).The increase in the MFV did not correlate with reduction of ICP. The cerebro vasculature remained responsive to changes in the CO2 and the pH despite severe head injury. Thermal Diffusion Method: Thermal diffusion method is currently being evaluated in clinical trials. The method involves placement of an subdural heat probe such that the rate of heat loss indicated the magnitude of cortical blood flows. This method is yet to find universal acceptance (REFERENCE NEEDED). It potential advantage in the clinical setting is that it provides regional flows in an area of interest. Animal studies also indicate that the thermal diffusion probe can breech the blood brain barrier and there by alter the regional flows by allowing diffusion of circulating substances like the catecholamines, which alter the local blood flows (). Jugular Venous Oxygen Saturation: The assessment of the Jugular Venous Oxygen Saturation can provide a valuable index of cerebral blood flow with regards to the cerebral metabolic needs. Continuous J V bulb saturation using fiber optic probes is feasible to optimize therapy in neurosurgical intensive care (REFERENCE NEEDED). Normally the difference between the AVjDO2 is about 4 -7 ml. Cerebral hyper perfusion is said to occur if the AVjDO2 is less than 4. However Cruz et al feel that AVjDO2 is not a reliable indicator of cerebral perfusion if hemoglobin is less than normal. They have therefore considered cerebral extraction of oxygen ,CEO2, as a more reliable parameter. CEO2 is the difference between SaO2 and SjO2. The normal range of CEO2 is 31.6 + 7.8%. Furthermore they have classified the increased cerebral oxygen extraction, oligemic cerebral hypoxia, into three grades. Grade I (mild): CEO2 20 -23%. Grade II (Moderate): CEO2 16 -19%. Grade III (severe) : CEO2 < 16%. These values represent 3, 4 and >4 standard deviation below the normal mean. Cerebral Angiography : The major role cerebral angiography in head trauma has been in the documentation of cerebral vasospasm after injury. A 30 -40% incidence of vasospasm in the large conducting arteries has been documented after head injuries ()()(). Documentation of spasm in the cerebral arteries has therapeutic implications. Since the flow beyond the spasm is pressure dependent any reduction in the pressure could potentially have severe consequences. Findings of vasospasm in the large arteries is also supported by Doppler studies (). ************************************************************************ THE REGULATION OF THE CEREBRAL BLOOD FLOWS IN HEALTH : The human brain has high metabolic requirements, but it lacks substrate reserves besides anaerobic energy generation leads to cerebral tissue acidosis, since lactic acid cannot easily penetrate the blood brain barrier (). It therefore requires a constant cerebral perfusion at both global and regional level. The arrangement of the cerebral vessels at the base of the brain forms the Circle of Willis. This unique vascular ring ensures that the regional cerebral blood flows do not depend on any single extracranial artery, but the arrangement, however, makes the assessment of cerebral blood flow difficult ,as we shall shortly discuss. The cerebral vessel are anatomically unique. The extra and intra cranial course of the arteries is long and they terminate in rather short arterioles (). The former represent the major site of cerebro vascular resistance, this is in contrast to other vascular beds where arterioles are the major site of vascular resistance (). The cerebral arteries are surrounded by perivascular sheath of leptomeninges which contains the CSF. Further nearly the entire cerebral circulation is chemically isolated from the general circulation by the blood brain barrier. The blood brain barrier offers not only a physical barrier by restricting the diffusion of substances but also by virtue of the layer of COMT and MAO enzymes surrounding the vessel it serves as an active chemical barrier as well (). This barrier may be lost acute hypertension, ischemia and focal trauma (). Intracarotid injections of hyperosmolar solutions also results in the disruption of the blood brain barrier due to shrinking of the cells and the opening of the tight junctions (). Physiologically too the cerebral circulation is unique in several respects. The cerebral vessels have a well developed autoregulation which ensures adequate cerebral blood flows across a range of cerebral perfusion pressures. The cerebral vessels are fine tuned to the metabolic needs of the brain and also respond dramatically to changes in Carbon dioxide and to a lesser extent to oxygen tension in the arterial blood. The underlying mechanism of metabolic autoregulation has been under close investigation, since this understanding would be crucial in modulating neuronal activity and altering the CBFs. It is presently thought that adenosine, adenosine pyrophosphate (), low oxygen tension(), neuronal metabolites(),and cyclooxygenase metabolites() may be involved to varying degrees in modulating cerebral circulation. Unlike most of the other vascular beds the cerebral vessels respond only poorly to neurogenic control. Although neurogenic control of cerebral circulation may be important in hypertensive subjects (), where due to autoregulation the cerebral vasculature is maximally constricted and even a slight reduction in vascular diameter under neurogenic control has a significant effect on the cerebral blood flow. The neurogenic control also protects the cerebral vasculature and the blood brain barrier during acute hypertension (), and is thought to influence vascular hypertrophy seen in chronic hypertensive states(), besides it influences the rate of CSF formation in the choroid plexus(). The Circle of Willis usually provides adequate cerebral collateral flows. There is evidence that the blood flowing in the internal carotid and the basivertebral system does not normally mix (). Also a complete occlusion of a carotid vessel attenuates but does not prevent the fall in pressure distal to the occlusion even in healthy subjects. Monitoring the stump pressure, i.e. the pressure distal to a temporary occlusion of the Internal Carotid Artery has been used as an indicator of the adequacy of the collateral flows in the circle of Willis during carotid endarterectomy()()(). Retrograde flow can occur from the Circle of Willis ,as in Subclavian Steal Syndrome,this can result in basivertebral insufficiency and syncope (). From the Circle of Willis paired anterior, middle and posterior cerebral arteries arise. Although these vessels supply discrete regions in the brain, however, there is anastomosis in the pial branches, enabling some collateral blood flow. The watershed zones lie between the distribution of these arteries and are the areas where ischemic damage occurs in severe sustained hypotension (). These areas are also the site of hemorrhage and the disruption of blood brain barrier in severe hypertension as that can be induced by lesions in nucleus tractus solitarius (). There is a dense network of capillaries in the brain. The capillary density is twice as much in the grey matter than in the white matter (). The capillary density increases considerably when the brain is subjected to chronic hypoxemia. There seem to be several A V shunts in the brain, but the magnitude of blood normally flowing through these shunts varies with the size of the microspheres used in the assessment. It can be a little as 2% with microspheres with 15 mc.m. diameter, but can be 8 -15 % with 7 - 10 micron spheres (). The brain has superficial and deep venous drainage. The superficial surfaces of the cortex and the cerebral hemispheres are drained by the veins which communicate with the dural sinuses. The deeper structures drain into the Great Vein of Galen and the Straight Sinuses and eventually into the Internal Jugular Vein. There are several communications between the intracranial and the extracranial veins (). Intracranial venous structures may also communicate with the venous drainage of the orbit and the sinuses. This can potentially contaminate data based on A - V concentration gradients, and there by affect cerebral blood flow calculations (). ************************************************************************* PATHOLOGICAL CHANGES IN HEAD INJURY: Despite considerable advances in our understanding of the regulation of cerebral circulation in health, the effects of head injury on the various aspects of CBF still remain obscure. Four factors control cerebral circulation. These include ,cerebral perfusion pressure ( pressure auto regulation), metabolic regulation, blood viscosity and CO2 reactivity (). The fifth factor that merits consideration is the loss of integrity of the blood brain barrier (). AUTOREGULATION IN HEAD INJURY : The ability of cerebral circulation to alter the cerebrovascular resistance in response to moderate changes in cerebral perfusion pressure is essential to maintain constant cerebral blood flow. Reduction of the perfusion pressure below the autoregulatory range results in tissue hypoxia while excessive pressure leads to cerebral oedema(). The mechanism of pressure autoregulation is yet to be fully understood. When viewed through the pial windows the vasodilation is not uniform and the large, the medium and the small arteries behave differently(). Traditional hypothesis regarding the mechanism of autoregulation include the neurogenic, the myogenic, the metabolic and have been reviewed elsewhere. The latter explanation recently been has partly attributed to the release of adenosine during hypotension(). Of late the interest has focused on the EDRF, Endothelial Derived Relaxing Factor. There is evidence that endothelial damage by a detergent as Triton X-100 impairs autoregulation in otherwise intact cerebral artery model. However the block of nitric oxide synthetase by nitro L arginine doesn't impair autoregulation (). The loss of cerebral auto regulation with head injury has been an area of conflicting experimental data. Bulk of the studies that were done before the universal application of CT scan, Glasgow Coma Scale and the Glasgow Coma Outcome Scale indicated that the cerebral autoregulation was not universally lost. In most of these studies the pressure autoregulation initially intact and was lost subsequently, bearing no relation to the outcome()()(). Since these studies considerable progress has been made. It has been recognized that mere alteration in the CBF in relation to the CPP may overestimate the incidence of impaired autoregulation since physiological swings may overlap with pathological changes. Bouma and Muilzelaar () have thus defined intact autoregulation as 0 < Delta % CPP/ delta % CVR < 2. Where CVR is given by CPP/CBF. Non invasive determination of cerebral blood flow using 133Xe as described by Obrist et al 1984, has been a major advance. Using the above definition of autoregulation or the loss of it, and by determination of the cerebral blood flow by using Obrist's method, Bouma et al could find no consistent correlation with clinical status, outcome or even a temporal profile (Table). It is not exactly known why autoregulation is lost in head trauma the proposed concept of a brainstem lesion has not been substantiated. The loss of autoregulation can alter responses in the CBF, CBV, and AVDO2 in response to changes in CPP and blood viscosity (Table ) (). Altered Metabolic Regulation in head injury : The AVjDO2 is considered as a reliable indicator of metabolic coupling. The alterations in CMRO2 during head trauma can effect the AVjDO2. Most studies indicate the CMRO2 is seldom increased after neurotrauma. The normal range of AVjDO2 is 4 - 7 ml /100 ml. A AVjDO2 less than 4 indicates CBF exceeding the metabolic needs, and an uncoupling of cerebral blood flow and tissue metabolism. Muizelaar et al 1989 () found a reduced AVjDO2 in 58% of 32 pediatric neurotrauma cases. In another series from the same center an AVjDO2 <2 was encountered in 153 of the 231 adult patients , and such a reduction was likely to be seen on the second day or after following a head injury. Cruz et al() have questioned the validity of the AVjDO2 as an indicator of cerebral oxygen extraction. They feel that at low hemoglobin levels the cerebral oxygen extraction is better reflected by the difference in saturation between the arterial and the jugular venous blood. They have therefore used another index known as Cerebral Extraction of Oxygen (i.e. CEO2) which is the difference between SaO2 and SjO2. In order to study the relationship between the CEO2 and the CPP, they observed the changes in the SEO2 and the CPP during spontaneous rises in the ICP despite treatment. They describe the Cerebral hemodynamic Reserve as : CHR = ( CEO2 f - CEO2 i)/ CEO2 i ( CPP f - CPP i)/ CPP i where i and f are the initial and the final value. They considered the CHR to be preserved if the it was greater than 0, and it was compromised if it was less than 0. Using this index they observed two groups of patients : Group I had eight patients with initially moderate head injury on the CT. Group II had twelve patients with severe injury. They found that the CHR with moderate injury was normal in the on day one but worsened on day two. There was also a correlation between the CT findings of increased tightness and the worsening of the CHR in this group. A cluster of closely related terms describe cerebral hyperemia after head injury, these include the Langfitt's concept of "vasomotor paralysis"() and Lassen's description of "luxury perfusion syndrome"(). Despite this, the reason for uncoupling of the cerebral blood flows and the cerebral metabolism in head trauma remains to be fully elucidated. Langfitt concept of vasomotor paralysis is an unlikely explanation since autoregulation is frequently present and CO2 reactivity is seldom lost in the cerebral circulation after neurotrauma(). Thus complete vasomotor paralysis is a rare feature. Similarly Lassen's description 'Luxury Perfusion' was originally described in stroke was attributed to lactic acidosis. However studies in head trauma indicate the peak of lactic acidosis occurs within 48 hours of injury, while cerebral hyperemia seldom peaks that early()(). Bouma and Muizelaar contemplate that in some instances this relative hyperemia may be due to inability of the neurons to utilize oxygen. They speculate that the injury may alter the enzymatic function within the neuronal mitochondria. Further if this hypothesis is true the low AVjDO2 is not a reflection of excessive blood flow but an underlying metabolic derangement (). Blood Viscosity Regulation of Autoregulation: The reduction of the blood viscosity causes a parallel reduction of the diameter of the cerebral arteries. This phenomenon was first reported by Muizelaar et al 1983() and has since been confirmed by Hudak et al 1989(). To quantify the phenomenon, a 23% reduction in the viscosity causes a 13% arteriolar constriction in diameter. Similarly during rebound from mannitol increase in the viscosity a 10% increase in viscosity is associated with a 12% increase in the vessel diameter(). According to the Poiseuille Hagen Equation: CBF = k CPP x d4 8nl Where k is the constant of proportionality, CPP is the perfusion pressure, d is the diameter, n is the coefficient of viscosity, l is the length of the tube. Since flow is proportional to the fourth power of resistance the significance od this 10% increase in the diameter of the vessel is considerable. In pathological circumstances the changes in viscosity autoregulation seem to go in parallel with the changes in pressure autoregulation. However it can be reasoned that a decrease in viscosity would result in increased flow, with autoregulation intact that increase in the flow would not be associated with an increase in intracranial blood volume due to cerebral vasoconstriction associated with hemodilution. However if the autoregulation was lost hemodilution would result in an increase in flow and increased blood volume (). CO2 Reactivity In Head Injury : A intact cerebral circulation responds by a 3% change in cerebral flows for each mm Hg change in CO2 ()()(). Although the CO2 reactivity can be impaired during head injury most studies indicate that it is usually intact. Experimental studies by Zimmerman et al indicate that there is an initial loss of CO2 reactivity which is restored in a few hours(). The mechanism of loss of CO2 reactivity probably involves endothelial damage, the consequent activation of cyclooxygenase and free radical generation. It is seen that N- acetyl cysteine a free radical scavenger restores CO2 reactivity in experimental traumatic brain injuries. N-acetyl cysteine does not block direct cerebral vasodilation by 2 - chloroadenosine, but blocks the action of arachidonic acid and bradykinin that vasodilate through free radicals. Thus, the effect of N acetyl cysteine on the cerebrovascular reactivity are probably mediate through free radical scavenging (). Following clinical head trauma that alteration of CO2 reactivity in the brain may not be homogenous. Using stable xenon CT CBF measurements, Marion and Bouma found that the CO2 reactivity ranged between 2 -4 % / mm Hg in 12 of the 17 patients, which lies within the physiologic range. However the overall response ranged from 1.3 -8.5 %. The potential hazards of such extreme responses include paradoxical inverse steal or in some situations severe vasoconstriction leading to tissue ischemia even infarction (). Such a vasoconstrictive response can be severely hazardous with decreased perfusion pressure, reduced O2 saturation of reduced cerebral blood flows all of which can occur during neurotrauma. Thus the indiscriminate use of hyperventilation can potentially be counter productive unless some form of appropriate cerebral monitoring is undertaken, metabolic,like Jugular Venous Saturation or AVjDO2, or electrophysiological. Marmarou 1992, analyzed the data of the Traumatic Coma Data Bank and has schematically represented the factors contributing to the ICP rise ( Figure ). He has proposed a new clinical indicator of the relation between change in intracranial blood volume in and the arterial carbon dioxide tension. The pressure volume curve is established by injecting or withdrawing the fluid within the cranial cavity. After the baseline ICP is reestablished arterial CO2 is allowed to rise or fall . The change in the ICP observed. Since the shape of the cerebral compliance curve is known the change in the CO2 can be correlated with the volume of fluid that needs to be injected or withdrawn from the cranial cavity ( Figure) . The Blood Volume Responsivity can therefore be a direct indicator of intracranial volume equivalence of changes in PaCO2. Head Trauma and the Blood Brain Barrier : In animal experiments the extent of loss of the blood brain barrier depends on the nature of injury, it's severity, the nature of the marker, and the site of assessment. Tanno et al (1992) assessed the permeability changes in the blood brain barrier after fluid percussive injury in rats. They found a wide spread increase in barrier permeability after fluid precussive injury. Also the maximum increase in the blood brain barrier permeability occurred within an hour of injury , however, at 24 hours the abnormal permeability was limited only to the site of injury at that remained permeable up to 72 hours. There is evidence from other studies that the loss of the blood brain barrier functions can be prolonged. These injuries are frequently associated with cell necrosis or hemorrhage. Persistent protein leak is also seen with stab injuries to the cortex. The consequences of the loss of the blood brain barrier in head injury can be severe. First, abnormal permeability of the blood brain barrier can expose the neural tissue to a variety of vasoactive substances like serotonin, histamine, excitatory amino acids, and prostaglandins. The vasogenic edema that results can be severe enough to cause a rise in the ICP and reduce the cerebral perfusion. The second consequence of the loss of the blood brain barrier is the ingress of cytotoxic substances like Ca,excitatory amino acids, membrane phospholipids derived products and free radicals into the CNS and this eventually leads to secondary brain injury. The third possible effect is that a damaged blood brain barrier impairs the availability of nutrients and can interfere with the removal of metabolic products. Finally, breech of the blood brain barrier can alter the clinical effects of drugs. ************************************************************************ THE EFFECT OF THE CEREBRAL BLOOD VOLUME ON INTRACRANIAL COMPLIANCE: It is evident that the loss of normal vasomotor control in neurotrauma can result in alteration of the intracranial blood volume. While this may not have a direct bearing on the cerebral blood flow there is evidence that it can influence the PVI. Using stable Xenon CT in combination with contrast transit time by rapid serial CT scanning one can determine the CBF and the CBV. In the clinical situation can be done during the initial CT scan. Bouma et al (1992) used this technique to study relation between the CBF, CBV and the PVI in fifteen patients. The finding of this group are shown in figure, while there is no relation between the cerebral blood volume and the CBF, there is an inverse linear correlation between the PVI and the CBV(). ************************************************************************** THERAPEUTIC IMPLICATIONS: Ischemia of the cerebral tissue in trauma could be a result of excessive demand or inadequate supply. Excessive demand in head injury is infrequently encountered. Most clinical studies indicate that the CMRO2 decreases after trauma. However experimental data indicates that after fluid percussion injury the CMRO2 shows a transient but significant rise is later followed by a period of sustained cerebral depression. This tissue hypermetabolism after injury may be mediated by neurotransmitter surge or excitatory amino acids release which show a significant rise after head injury. While, inadequate supply may be due to systemic hypotension, spasm in the large cerebral vessels, or failure of microcirculation. Therapeutic hypothermia to reduce CMRO2 has been sporadically in neurosurgery since Bigelow in 1950 first described brain protection from global ischemia. Of late there has been a resurgence of interest in moderate hypothermia. Clifton et al 1992 found no major complications associated with this level of hypothermia although further studies are needed before the outcome data can be evaluated. It is now clear that pressure autoregulation in the cerebral bed is often preserved after injury, yet, it is well established that hypotension in head trauma is potentially lethal. Due to the presence of the spasm in the cerebral vasculature it is essential that adequate perfusion pressure is maintained. The question that arises is when should we consider treating hypertension after neurotrauma. Excessive arterial pressure can cause hydrostatic cerebral edema in areas where pressure autoregulation is impaired. It can aggravate intracranial bleed. Hypertension is known to breech the blood brain barrier, which may already be damaged during head injury. Further focal loss of pressure autoregulation can theoretically redistribute blood to traumatized areas resulting in the enlargement of the contusion and exacerbation of edema. Thus, hypertension in the absence of cerebral vasospasm is potentially hazardous. The finding that impaired cerebral perfusion occurs early after head injury has encouraged workers to raise the blood pressure in severe cases. Bouma et al 1992, considered it clinically justifiable to raise the blood pressure with phenylephrine in 4 patients with a CBF < 18 ml/100 gm /min and a AVjDO2 > 8 ml/100 ml. The group found consistent improvement in the in AVjDO2 difference and the CBF which was associated with improvement in clinical and electrophysiological parameters. In another series the arterial blood pressure was supported by vasopressor and fluids aimed to maintain a cerebral perfusion pressure of 84 mm Hg. In this series of 34 cases 50% patients with had good neurological outcome and a significant reduction in mortality. While a judicious increase in arterial pressure may improve cerebral circulation distal to vasospasm, it may not be able to improve circulation at microscopic level. The exact sequence of molecular events that occur after neurotrauma still eludes us. There is a significant surge of prostaglandins after injury. This rise in prostaglandins could be triggered by neurotrauma, ischemia, seizures or massive neurotransmitter ,e.g. ACh, release. Massive surges in Prostaglandins may case release of free radicals and can potentiate neural damage. A rise in PGB2 has been documented after injury. PGB2 is a potent vasoconstrictor and causes platelet aggregation. A similar rise ia PG D2, PG F2& and PG B2 has been documented using microdialysis within one hour of penetrating brain injury. PG E2 and prostacycline metabolites showed a delayed peak six hours after injury. PGE2 is known to rise after fluid percussion injury. It is primarily a neuromodulator and in primates reduces the CMRO2, intraventricular injection cause sedation. PGE2 in rats potentiate adrenergic vasoconstriction in rat's pancreatic and renal arteries. Thus Prostaglandins can effect several aspects of cerebral circulation and these effect may be species specific. Jensen et al used indomethacin in five patient with severely raised intracranial pressure not responding to conventional therapy. Indomethacin decreased the CBF and the ICP and increased the AVjDO2, but was associated with good neurological outcome. Cerebral vasoconstriction was not associated with increase in lactate oxygen index. In animal experiments indomethacin also demonstrates similar effects. The role of calcium channel blocking drugs in cerebral vasospasm after sub arachnoid hemorrhage and aneurysm surgery is well documented. The potential benefits of this group of drugs in head injury could arise either from minimizing the ischemic insults or neuro protection. The British Finnish Cooperative Head Injury Trial Group evaluated the efficacy of nimodipine in severe head injury. In all 176 patients received nimodipine 2 mg/hr, there was a 53% favorable outcome in this group, while in the 175 placebo controlled patient there was 49% favorable outcome. These changes were not statistically significant. However the authors justify the use of calcium channel blockers in head injury as the secondary brain insults occur even during hospitalization and could benefit with treatment.It is hoped that a larger trial would validate the use of the drug in head trauma. There seem to be more than one type of Calcium Channels involved in augmenting cerebral blood flows and providing neuro protection during ischemic insults. Nimodipine acts on the dihydropyridine sensitive L type of channels. But the major route of Calcium influx into neurons during ischemic injury is through voltage sensitive high threshold R type of channels. These are not affected by nimodipine however they can be blocked by CNS 2103, a compound derived from snake venom, which is under investigation. There is also growing interest in the presynaptic N type of channels, which modulate neurotransmitter release. These channels can be blocked substitute guanidine like CNS 1145. By blocking Calcium channels in the pre synaptic terminal it is hoped that the glutamate release is prevented and the sequence leading to cell death is aborted. Head elevation of neurosurgical patients can influence cerebral perfusion by altering the arterial pressure, the venous pressure and the ICP, besides it can also alter the cardiac output. Feldman et al studied the effect of change from 0 - 30 degrees head elevation on in 22 head injured patients and found a significant decrease in the ICP with no statistically significant change in cerebrovascular resistance, CPP, or CBF. Besides, the CMRO2 and A-Vj difference of lactate also did not change statistically. The use of osmotic diuretics in acute head trauma can affect the cerebral blood flows by two ways. First, being hyperosmotic they can reduce the ICP by setting an osmotic gradient across the blood brain barrier which results in the withdrawal of fluid from intracellular compartment. It has been shown that in human head injuries mannitol increase the specific gravity of white matter by reducing the water content. The second effect is hemodilution due to vascular expansion which is associated with cerebral vasoconstriction. However sudden infusions can also cause expansion of the blood volume and transiently raise the ICP. In the presence of cerebral autoregulation and an intact blood brain barrier the benefits of mannitol are obvious. But if head injury is severe and the blood brain barrier and autoregulation is lost. Mannitol infusions can raise the mannitol infusions can increase the cerebral blood flows and the cerebral blood volume, with potential deleterious effects. Experimental evidence in cats involving measuring the regional cerebral blood flow by hydrogen clearance show that mannitol infusion is associated with a reduction of the ICP and the increase in the CBF. This benefit is transient. If the subsequent increase in the ICP and the reduction in the CBF are treated by an additional dose of mannitol the second dose is followed by an even more severe rise in the ICP. The role of hyperventilation in head injured patients has been under critical review. Hyperventilation has been shown to improve outcome in severe head injury ( Gordon and Rossanda, 1970). But experimental studies have shown that hypertension can cause intense vasoconstriction leading to reduction of cerebral blood volume and cerebral blood flows. Further there is a possibility the sustained hyperventilation could alter distribution of regional blood flow. When studied in a swine model Madsen (1990) found no change in CO2 reactivity as compared to the normal tissues. The regional blood flows to the contused region before hyperventilation were low and during hyperventilation declined to ischemic levels at risk of infarction. Muizelaar et al describe a randomized clinical trial in 113 patients. The study compared normoventilation (41 patients), hyperventilation (36 patients) and hyperventilation plus THAM ( 36 patients). Hyperventilation if sustained can decrease the CSF bicarbonate which is an important buffer. Thus the administration of THAM was aimed to restore the buffering capacity.the main results of their study were that sustained hyperventilation prophylactically retarded recovery and that worse prognosis at 3 months and 6 months after wards although not at 12 months. the concurrent use of THAM seems to mitigate the deleterious effects of prolonged hyperventilation. Yoshida and Marmarou also studied the bioenergetics in laboratory using magnetic resonance spectroscopy in cats using the same groups. Their findings included that THAM treatment ameliorated lactate production during hyperventilation. Brain edema was less when hyperventilation was combined with THAM. Finally when the ratio of phosphocreatinine to inorganic phosphate (PCr/Pi) was studied as a marker for recovery of oxidative stores, there was no recovery with sustained hyperventilation but approached normal values if hyperventilation was combined with THAM. ************************************************************************ BASICS OF RECOVERY ROOM MANAGEMENT AND RESPIRATORY THERAPY THE RECOVERY ROOM: Recovery Room Organisation Criteria for Admission To The Recovery Room Recovery From Anesthesia: Pulmonary Complications Laryngospasm Arterial Hypoxemia Circulatory Complications: Hypotension Hypertension Arrythmias Agitation Pain Renal : Oliguria Bleeding Hypothermia Post operative Ventilation RESPIRATORY THERAPY: Oxygen Therapy Techniques: Nasal Cannula Face Mask : Simple , Parital Rebreathing, Non rebreathing. Air Entrainment Hazards of Oxygen Therapy Retrolental Fibroplasia Carbon Dioxide Retention Absorption Atelectasis Pulmonary Oxygen Toxicity Humidification : Passover humidifiers, Bubble through Nebulisers:Jet Nebulisers, Ultrasonic Nebulisers Noscomial Infections Bronchial Hygiene Postoperative Respiratory Therapy Deep Voluntry Breathing IPPB Incentive Spirometry Exhalation Maneuvers ******************************************************************************