1. Hypothermia and DHCA Abhi mishra Moderator: Dr Aveek

2. Hypothermia Used first for TBI by Fay in 1945 Bigelow performed experiments in 50`s I`st ASD closure in 1952 by dr john lewis under hypothermia After the first years of enthusiasm, however, deep hypothermia was vastly abandoned in noncardiac surgery During the subsequent 30 years as a result of thefrequent occurrence of severe complications such as systemic infections, fluid and electrolyte imbalances and cardiovascular instability Resurgence in use since 80`s with mild

3. Basis for usage Rate of biologic reactions changes linearly with temperature Rate of biologic reactions(due to enzymatic involvement) however decreases exponentially with temperature Q10 : factor by which rate changes over a temperature change of 10 C For most biologic reactions value of Q10 is in range of 2-3(310k-300k)

4. VO2 vs temperature

5. In humans CMRO2 decreses 5-7%/C fall in temperature This low metabolic rate maintains the demand and supply ratio even at low blood flows due to low requirement In other words hypothermia increases the tolerance of cells towards ischemia Window period before ischemic injury occurs is directly related to degree of hypothermia

6. Degrees of hypothermia Mild : 32-34 C Moderate : 25-32 C Deep : 14-25 C Electrical silence : 12-18 C

7. possible sites of action Decreased excitotoxicity Decreased necrosis and apoptosis Decreased microglial cell activation Oxidative stress modulation Decreased inflammation post ischemia

8. ExcitotoxicityIschemia:ATP depletion which leads toloss of ion gradients and accumulationof intracellular K+ and Na+ Glutamate release and decreased uptake Excessive Ca+ influx and cellular hyperexcitability

9. Late consequences Cytotoxic edema Vasogenic edema Dysfunctional BBB : increased interstitial water movement and rise of pericellular hydrostatic pressure

10. Necrosis and apoptosis Hypothermia decreases cytochrome c release Decrease caspase activation,DNA fragmentation

11. Decreased microglial activation Less production of IL-6 and NO Inhibition of glutamate induced NO synthesis Supression of neutrophil accumulation

12. Acid base balance pH: 7.40 & pCO2: 40 mm of Hg at 37 deg C. The solubility of gases increases with fall in temperature The change in [H+] and pH that occurs with change in temperature is independent of a change in CO2 content, and therefore does not depend on the change in CO2 solubility with the temperature change

13. All acids and bases, including water, exist insolution in equilibrium between the undissociatedform and the ionized components of the parentmolecule. The dissociation constant (K) is theequilibrium ratio of the product of theconcentrations of the ionized components to theunionized component. For water at 25C, theequilibrium dissociation equation is as follows:

14. pH and pN pH= - log [H+] i.e ; - log 1* 10-7 = 7 Dissociation is directly proportional to temperature In temperature range seen in clinical CPB (approximately 15C to 40C), the dissociation constant of water increases from 0.451 10-14 to 2.919 10-14 Change in [H+] from approximately 67 nmol/L at 15C to 170 nmol/L at 40C

15. Water(universal solvent) Hence water changes from weak base to weak acid with increase in temperature The major importance of this concept is that water is the fundamental solvent of all biologic systems and the dissociation of virtually all weak acids and bases in biologic solutions follows the same pattern as that described for water

16. Blood buffers At normal body temperature (37C), blood and tissue fluids are alkaline relative to water at the same temperature A number of buffer systems create and maintain this relative alkalinity so that the ratio of [OH-] to [H+] remains constant at approximately 16:1 despite temperature variation As temperature changes, the intrinsic dissociation of these buffer systems also changes to maintain the ratio of [OH-] to [H+] constant

17. Importance of histidine A major buffering system responsible for this is the imidazole moiety of the amino acid histidine, which is commonly found in body proteins. The pKa of histidine is close to 7.0 at body temperature confers potent buffering capacity for maintaining a constant ratio of [H+] to [OH-] despite significant changes in the absolute concentration of each as temperature varies

18. Ectothermic animals pH strategy

19. What is alpha? The ratio of the unprotonated histidine imidazole groups to H+, a value known as alpha, remains constant Total CO2 also remains constant pH changes as per the changes in temperature Reaction kinetics of numerous respiratory enzyme systems show optimal catalytic function with temperature change when the pH of the reaction medium parallels the temperature mediated pNH2O change This method is hence known as alpha stat strategy

20. pH stat Alternative method of acid-base strategy is pH-stat. With this method, pH is the value that is maintained constant at varying temperatures. Hibernating mammals maintain a pH-stat strategy These animals hypoventilate as they hibernate, the tissue CO2 stores increase, and intracellular pH becomes acidotic in most tissues. This acidotic state causes a further depression of metabolism that may be useful by further decreasing the energy consumption of nonfunctioning tissues, such as skeletal muscle, gastrointestinal tract, and higher brain centers. In contrast, active tissues, such as heart and liver, adopt a different strategy by actively extruding H+ across their cell membranes to maintain intracellular pH at or near the values predicted by the -stat methodology. Therefore, hibernating mammals are able to vary their intracellular-to-extracellular pH gradient differently in different tissues, depending on the state of metabolic

21. Organ function Hypothermia causes a decrease in blood flow to all organs of the body Skeletal muscle and the extremities have the greatest reduction in flow, followed by the kidneys, splanchnic bed, heart, and brain. Despite this decrease in flow, differences in the arteriovenous oxygen content are seen to either decrease or remain unchanged, which implies that the oxygen supply is adequate to meet the metabolic requirements

22. Heart With cooling, heart rate decreases but contractility remains stable or may actually increase Dysrhythmias become more frequent as temperature decreases and may include nodal, premature ventricular beats, atrioventricular block, atrial and ventricular fibrillation, and asystole The mechanism of this dysrhythmogenic effect is unknown but may involve electrolyte disturbances, uneven cooling, and autonomic nervous system imbalance. coronary blood flow is well preserved during hypothermia, it is unlikely that myocardial hypoxia plays a role in the genesis of these dysrhythmias

23. Pulmonary system The pulmonary system is characterized by a progressive decrease in ventilation as the temperature is lowered Physiologic and anatomic dead space increases during dilation of the bronchi by cold. Gas exchange is largely unaffected

24. Renal function The kidneys show the largest proportional decrease in blood flow of all the organs. Hypothermia increases renal vascular resistance, with diminished outer and innercortex blood flow and oxygen delivery. Tubular transport of sodium, water, and chloride are decreased. Urine flow may be increased with hypothermia, but this effect can be masked by the stress-induced release of arginine vasopressin The ability of the hypothermic kidney to handle glucose is impaired, and glucose often appears in the urine Hemodilution in combination with hypothermic CPB improves renal blood flow and protects the integrity of

25. Metabolic changes Hepatic arterial blood flow is reduced Decrease in metabolic and excretory function of the liver Marked hyperglycemia due to decreased endogenous insulin production,glycogenolysis and gluconeogenesis because of increases in catecholamines Even if exogenous insulin is administered, its efficacy is reduced during hypothermia

26. Vascular system Tissue water content is increased due to hemodilution. Cell swelling and edema occur, which may be related to an accumulation of sodium and chloride within cells secondary to a decrease in reaction rates of membrane Na+ -K+ -ATPase SVR and PVR typically rise with cooling below 26C Arteriovenous shunts appear at low temperatures and may cause a further diminution in tissue oxygen delivery The increase in blood viscosity occurs because of fluid shifts, with loss of plasma volume from capillary leak and cell swelling The red blood cell volume remains unchanged although the hematocrit rises. Red blood cell aggregation and rouleaux formation can occur, further impeding blood flow These changes can be attenuated by adequate anesthesia, hemodilution, heparinization, and the use of vasodilators. Thrombocytopenia by a reversible sequestration of platelets in the portal circulation

27. DHCA The most dramatic application demonstrating the protective effects of hypothermia is in DHCA. Systemic temperatures of 20C to 22C or less are used to allow cessation of the circulation In pediatric cardiac surgical patients (particularly those weighing < 8 to 10 kg) the repair of complex congenital cardiac lesions is often facilitated by the asanguineous surgical field provided with circulatory arrest It is often used in procedures requiring occlusion of multiple cerebral vessels, particularly repair of aortic arch aneurysms. It may be used to enhance surgical exposure and speed in procedures that could lead to uncontrollable hemorrhage

28. Organ protection during DHCA Hypothermia Pharmacological adjuncts Perfusion strategies Topical external cooling of the head optimized acid-base management pump prime modifications leukocyte depletion The degree of hemodilution strategies of cooling and rewarming

29. Conduct of DHCA(temperature)The cooling phase should be gradual and long enough(20-30 mins) to achieve homogenous allocation of blood to various organs and to prevent a gradual updrift of temperature during DHCA Rapid cooling might create imbalance between oxygen delivery and demand by increasing the affinity of hemoglobin to oxygen. This increased affinity combined with extreme hemodilution from the priming solution for CPB might lead to cellular acidosis before DHCA

30. Degree of hypothermia required Approximately 60% of the brains energy consumption is used to transmit nerve impulses; the remaining 40% is used for preservation of cellular activity. Electrocerebral silence occurs at about 17C nasopharygeal temperature Although animal evidence suggests better neuroprotection at temperatures of 8-13 C High degree of choreathetosis was seen in humans subjected to these temperatures post.op Hence general practice is to cool to 15-20 C before instituting circulatory arrest

31. Oxgen dissociation curve Theoretically, hypocarbia (and increased pH) result in a leftward shift of the oxyhemoglobin dissociation curve, which causes oxygen to be less readily available to the tissues However, more oxygen is dissolved in the plasma during hypothermia, so that these two effects tend to cancel out each other

32. Topical cooling Delay in temperature equilibrium may occur because of occlusive vascular disease that reduces cerebral perfusion Icepacking of the skull enhances cerebral hypothermia via conduction across the skull Helps to keep body temperature around 10 to 13C Prevents undesirable rewarming of the brain Systems of continuous cooling of the head during DHCA recently have been developed Consist of a cooling cap with an incorporated circuit of continuously circulated water at a

33. Boston trial Boston Circulatory Arrest Trial prospectively observed the neurological outcome of 171 neonates with Dtransposition of the great arteries that were randomized either to DHCA or to low- flow CPB for the arterial switch operation In immediate post op period incidence of seizures was higher in DHCA group One year after surgery risk of delayed motor development was more in DHCA group These risks were proportional to amount of time spent in DHCA

34. Duration of DHCA

35. Rewarming Rewarming increases CBF and the risk of embolization,cerebral edema, and hyperthermic brain injury During rewarming extracranial sites of temperature monitoring underestimate brain temperature by about 5 to 7C May result in brain hyperthermia during rewarming Perfusate temperature should not exceed core body temperature by more than 10C; to stop rewarming when core body temperature is 36C (esophageal) or 34C (urinary bladder) and for perfusate temperature not to exceed 36C Relative hypothermia (36C, esophageal; 34C, urinary bladder) might be beneficial If EEG shows electrical hyperactivity decrease in temp./deepening of anaesthesia should be instituted Initial reperfusion with relatively cold blood at low pressures allows washout of accumulated metabolites and free radicals and provides substrates for high-energy molecules. A period of initial hypothermic perfusion has been shown to improve neurologic outcome

36. Cerebral blood flow decreases with hypothermia esp. with alpha stat management Autoregulation may be impaired at moderate to deep hypothermia CBFV is not detectable below CPP of 9mm of Hg induced by low flow state A minimum CPP of at least 13 mm of Hg was required to attain a measurable CBFV

37. Cerebral blood flow determinats

38. Alpha or ph stat Acid-base management may be critical in the setting of deep hypothermia. Proponents of the -stat method suggest that pH-stat management may put the brain at risk for damage from microemboli, cerebral edema, or high intracranial pressure, or may actually predispose to an adverse redistribution of blood flow (steal) away from marginally perfused areas in patients with cerebrovascular disease. On the other hand, proponents of the pH-stat strategy suggest that enhanced CBF may be helpful in improving cerebral cooling before the initiation of circulatory arrest. In fact, total CBF is increased, global cerebral cooling is enhanced, and brain blood flow is redistributed during pH-stat management.

39. Alpha or ph stat An increased proportion of CBF is distributed to deep brain structures (thalamus, brainstem, and cerebellum) with ph stat However, other data suggest that cerebral metabolic recovery after circulatory arrest may be better with the -stat method than with the pH-stat mode This variation in results has led some authors to advocate a crossover strategy in which a pH-stat approach is used during the first 10 minutes of cooling to provide maximal cerebral metabolic suppression, followed by an -stat strategy to remove the severe acidosis that accumulates during profound hypothermia during pH-stat. This approach appears to offer maximal metabolic recovery in animals

40. Alpha or ph stat -stat management will result in lower cerebral flows than those seen with pH-stat management However, because of the lowered metabolic demands, a lower CBF may be appropriate and indicative of a maintained coupling of blood flow and metabolic demand Coupling of CBF and metabolism that was independent of cerebral perfusion pressure (CPP) within the range of 20 to 100 mm Hg when -stat management was employed Cerebral autoregulation was abolished and CBF varied with perfusion pressure when pH-stat strategy was used

41. pH stat Alpha stat

42. When to use alpha stat ? Throughout hypothermia in adult patients generally in which luxury flow will increase the embolic load During rewarming in pediatric patients as it provides better cerebral metabolic recovery CBF decreases linearly with the decrease in temperature, whereas CMRO2 drops exponentially.The net result is that CBF becomes more luxuriant at deep hypothermic temperatures. At normothermia, the mean ratio of CBF to CMRO2 is 20:1, and at deep hypothermia, the ratio increases to 75:1

43. When to use pH stat then? In pediatric patients with aortopulmonary collaterals cerebral cooling can problematic It appears that the addition of CO2 during cooling enhances cerebral perfusion and improves cerebral metabolic recovery in this group An increase in pulmonary vascular resistance and a decrease in pulmonary blood flow with the pH- stat strategy also helps Also to provide homogenous cooling while instituting hypothermia

44. Metabolic supression andrecovery

45. Targets for pharmacological protection

46. Pharmacological adjuncts

47. Degree of hemodilution In past hematocrits in range of 10-30 have been used Hemodilution is not only a problem for red cell- dependent gas transport, but also for platelet and humoral factor-dependent coagulation and protein dependent intravascular oncotic pressure Recent data suggests maintaining hct in range of 25-30 provides better outcomes Higher hematocrits improve tissue flow and metabolism and decrease leukocyte and endothelial cell activation

48. Monitoring Standard ASA monitoring Arterial catheter Pulmonary artrey cath if indicated TEE Jugular bulb oximetery and temperature NIRS Trans cranial doppler EEG,BIS SSEP

49. TEE Cardiac function before and after DHCA Examination of aorta Confirming canula placement Assesing volume status Determining adequeacy of repair Detecting intra cardiac air

50. Temperature As 99% of jugular blood flow originates from brain circulation it is regarded as gold standard During cooling phase nasopharyngeal temperature corresponds to jugular temp. During rewarming all sites lag behind Caution has to be exercised to avoid hypothermic insult

51. Jugular oximetery Oximeter catheters transmitting three wavelengths of light are used Directly and continuously measure cerebral venous oxygen saturation recent study observed a much wider 45% to 70% range in healthy subjects. Furthermore, the 95% confidence interval of the low threshold was 37% to 53%

52. Limitations Sjvo2 represents a global measure of venous drainage from unspecified cranial compartments Imaging demonstrated substantial hypoxic regions within the cerebral parenchyma that were invisible to Sjvo2 Accurate measurement using jugular oximetry requires continuous adequate flow past the catheter. Low- or no-flow states such as profound hypoperfusion or complete ischemia render Sjvo2 unreliable

53. NIRS Human skull is translucent to infrared light Regional hemoglobin oxygen saturation (rSo2) may be measured noninvasively with transcranial near-infrared spectroscopy (NIRS) NIRS measures all hemoglobin,pulsatile and nonpulsatile, in a mixed microvascular bed composed of gas-exchanging vessels with a diameter less than 100 m. The measurement is thought to reflect approximately 75% venousblood

54. High baseline variability among subjects Values < 50% considered low Used to monitor trends Fall of more than 20% especially if prolonged has been associated with neurologic injury Has been used during cooling to achieve 95% value signifying maximal metabolic supression Value keeps on decreasing during DHCA and decay is faster at higher temperatures

55. NIRS during DHCA During DHCA value decreases to a nadir of about 70% of baseline over 20-40 mins At this point apparently there is no additional uptake by neural tissue Interestingly the time of this plateuing corresponds to maximum duration of DHCA found out by the studies i.e 40 mins

56. Uses Used as transfusion trigger Guide to supplemental cerebral perfusion Defines limits of autoregulation Anesthetic adequacy

57. Trans cranial doppler

58. Other usesCan also be used to calculate CMRO2 in conjunction withSjVO2

59. EEG To establish electrical silence before onset of DHCA Temperature range differs Only signifies loss of impulse conduction and tells nothing about baseline metabolism Difficult to interpret,interference BIS monitoring in some cases is reported to detect cerebral hypoperfusion & cerebral air embolism

60. Multi modality neurophysiologicmonitoring

61. Alternative strategies DHCA is not free from ischemic complications To counter this many perfusion strategies have been developed which include intermittent cerebral perfusion low flow cardiopulmonary bypass regional cerebral perfusion(ACP& RCP)

62. Intermittent low flow perfusion systemic recirculation for 10-minute periods every 20 minutes during DHCA to prevent cerebral anaerobic metabolism during long periods of circulatory arrest. This strategy is utilized commonly during pulmonary thromboendarterectomy This technique is not necessarily an alternative to ACP and RCP

63. Low-flow CardiopulmonaryBypass low-flow CPB was superior to DHCA with respect to high-energy phosphate preservation, cerebral oxygen metabolism, CBF, cerebral vascular resistance, and brain lactate levels. The minimum safe level of blood flow has not been established For infants, a minimal cerebral perfusion pressure of 13 mm Hg was necessary to maintain flow, and flow rates of about 50 mL/kg/min were required

64. Retrograde cerebral perfusion RCP is performed by infusing cold oxygenated blood into the superior vena cava cannula at a temperature of 8 C to 14 C via CPB The internal jugular venous pressure is maintained at less than 25 mm Hg to prevent cerebral edema Site proximal to the superior vena cava perfusion cannula and zeroed at the level of the ear

65. Patient is positioned in 10 degrees of Trendelenburg To Decrease the risk for cerebral air embolism and prevent trapping of air Flow rates of 200 to 600 mL/min usually can be achieved

66. Advantages The technique provides the opportunity for thorough deairing of vessels of the arch. Cerebral cooling is facilitated and toxin removal occurs. It may also remove solid emboli from the arterial branches of the arch. Avoids manipulation of the atheromatous arch vessels and it allows removal of some cannulae from the surgical field The technique of DHCA with RCP is a reasonable approach for neuroprotection during aortic arch surgery in the setting of adequate institutional experience (ACC/AHA Class IIa recommendation; level of evidence B

67. Disadvantages The disadvantages include the scanty evidence that blood reaches the cerebral target, an assumption that may provide false confidence. During RCP, only a minimal amount of blood (not more than 3% to 10%) is directed to the brain, whereas more than 90% is deviated through the azygos to the SVC or entrapped in the cerebral venous sinuses

68. Circuit in RCP

69. Anterograde cerebral perfusion Perfusion of brain with oxygenated blood independently of the rest of the body At physiological flow and pressure of 10-20 mL/kg/min and >50 mm of Hg Potential to prolong the safe time of circulatory arrest Improved cerebral cooling due to heterogeneous flow, and its potential application with moderate instead of deep hypothermia

70. Non selective cerebral perfusion Non-selective ACP (NSACP), or hemispheric perfusion, refers to selective cannulation of the right axillary artery with lefthemispheric perfusion dependent on a patent Circle of Willis Advantages of axillary artery cannulation include its use as an access for conduct of CPB and the relative freedom of the axillary artery from dissection and atherosclerotic disease, thus, decreasing the incidence of atheroemboli. Potential complications of axillary artery cannulation include insufficient flow, inadequate right upper limb perfusion, lymphocele, and brachial plexus injury Perfusion of both hemispheres is compromised in cases of absent communication at the Circle of Willis, which can be present in up to 20% of patients

71. Non selective anterograde perfusion

72. Selective anterograde cerebralperfusion Canulation of carotid artery and the innominate artery, either directly or through a tube graft. The drawbacks of this approach include the needed dissection of these key vessels May lead to vessel injury or embolization and the inconvenience of added cannulae in the operative field

73. Circuit for selective cerebralperfusion

74. ACP vs RCP