Combined use of isoflurane and sodium nitroprusside during active rewarming on cardiopulmonary bypass: a prospective, comparative study.SP Ambesh, M Chattopadhyaya, PV Saxena, TS Mahant, AK Ganjoo
Department of Anaesthesiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - 226 014, India. , India
AIMS: To evaluate and compare the effect of isoflurane, sodium nitroprusside (SNP) and combined use of isoflurane and SNP on body rewarming and haemodynamic stability during active rewarming on cardiopulmonary bypass (CPB). SUBJECTS AND METHODS: In a prospective, randomised study 75 adult patients scheduled for coronary artery bypass grafting (CABG) under CPB were studied in three groups of 25 patients each. During active rewarming, patients of group I received SNP infusion in CPB, group-II received isoflurane through vaporiser in gas circuit of the CPB machine and group III received a combination of isoflurane inhalation (0.2-0.5%) + SNP in low doses (<1mg/kg/min). RESULTS: Mean requirements of SNP to achieve maximum pump flow during rewarming were 1.48 -/+ 0.65 mg/kg/min (range 0.3-3.5 mg/kg/min) in group I and 0.75 -/+ 0.25 mg/kg/min (range 0.2-0.85 mg/kg/min) in group III. Mean isoflurane concentration required to achieve maximum pump flow during rewarming was 0.95 -/+ 0.35% (range 0.2-1.5%) in group II and 0.35 -/+ 0.1 (range 0-0.4%) in group III. The requirements of SNP and isoflurane in group III were significantly less than group I and II (p<0.001). The haemodynamic stability was better in SNP + isoflurane group with significantly lesser requirement of inotropes. Four-scaled assessment for rewarming evaluation failed to show significant statistical difference amongst the groups. CONCLUSIONS: All three drug regimens were equally effective in terms of uniform rewarming of the body on CPB. However, combined use of SNP and isoflurane in low doses provides haemodynamic stability during CPB and is superior to either drug alone.
Keywords: Adult, Aged, Anesthetics, Inhalation, therapeutic use,Cardiopulmonary Bypass, Comparative Study, Drug Combinations, Female, Hemodynamics, Human, Isoflurane, therapeutic use,Male, Middle Age, Nitroprusside, therapeutic use,Prospective Studies, Rewarming, Vasodilator Agents, therapeutic use,
During cardiopulmonary bypass (CPB), moderate degree of systemic hypothermia (280 to 300C) is commonly practised in order to reduce systemic oxygen consumption and to slow the rate of warming of the heart when hypothermic (40C to 100C) myocardial protection techniques are used. Total body cooling or rewarming is not uniform at the point when perfusate and venous outflow temperature equalise, because many tissues have very low blood flows. Such tissues are slow to cool, and once cooled, are slow to rewarm. Rewarming during CPB falls short of restoring the heat loss during cooling by almost 33% despite a normal core temperature at the end of CPB. After moderate hypothermia during rewarming period on bypass the core rewarms faster than rest of the body as it receives high proportion of cardiac output. Despite spending few minutes time with core temperature at 370C on bypass severely constricted peripheral vasculature may not adequately dilate and fail to rewarm adequately. During early post bypass period and after resumption of normal pulsatile flow heat is transferred from the warm core to the periphery resulting in to significant afterdrop and therefore significant decrease in core temperature. Incomplete rewarming results in a 10C to 30C decline in core temperature in the first 2 to 6 hours after the operation (afterdrop), with potentially deleterious consequences.,
Various methods, such as heating blanket, high ambient temperature, warmed fluids, heated humidified gases, sodium nitroprusside (SNP) infusion, and isoflurane administration, have been used to achieve uniform rewarming before termination of cardiopulmonary bypass. The SNP infusion is widely used because of its profound dilatory effect on arterioles and thereby assisting in effective rewarming of the body. However, the use of SNP has been associated with wide fluctuation in mean arterial pressure (MAP), requiring frequent adjustment of SNP infusion and addition of vasopressures e.g., dopamine or norepinephrine, infusion in the event of profound hypotension. Isoflurane causes satisfactory peripheral vasodilatation and improves the uniformity of rewarming on CPB. We postulated that a combination of isoflurane (0.2-0.5%) with low dose SNP infusion (<1?g/kg/min) may achieve uniform rewarming with better haemodynamic stability. The present study is a prospective randomised trial in order to test our hypothesis.
Seventy-five patients of either gender, aged 38 to 76 years, undergoing coronary artery bypass grafting (CABG) were included. Patients with poorly controlled diabetes, severe hypertension, peripheral vascular disease, peripheral neuropathy, poor left ventricular function and with history of recent myocardial infarction in last three months were excluded from the study. All patients received oral diazepam (5-10 mg), about two hours before induction of anaesthesia. In operation theatre pulse oximetry and continuous ECG lead II monitoring were instituted. Radial artery cannulation was done for direct arterial pressure monitoring.
Induction of anaesthesia was achieved with intravenous fentanyl (10 ?g/kg), midazolam (0.1 mg/kg) and thiopental sodium (2-3 mg/kg). Vecuronium (0.1 mg/kg) was used for muscle paralysis and endotracheal intubation. Intermittent positive pressure ventilation (IPPV) of lungs was started with a mixture of 0.2 to 0.5% isoflurane (Vapor 19.3, Dragerwerk AG Lubeck, Germany) and 50% oxygen in air. Respiratory rate and tidal volume were adjusted to maintain end tidal carbon dioxide (EtCO2) between 35 to 40 mmHg. Right internal jugular vein was cannulated to monitor central venous pressure (CVP). Continuous iv infusions of fentanyl (5?g /kg/hr), midazolam (0.1 mg/kg/hr) and vecuronium (0.1 mg/kg/hr) were started. The ambient temperature of operative theatre was kept between 20 to 220C with relative humidity of 40-60%. The central core and intermediate thermal zone temperatures were monitored using thermister probe (HP 78534C monitor, Hewlett Packard, USA) in nasopharynx and rectal region, respectively. The temperature of peripheral thermal zone was monitored by skin surface temperature sensor placed on the thumb-pulp.
In all patients, midsternotomy was used for opening the chest. Following cannulations of superior vena cava, inferior vena cava and aorta, CPB was instituted using membrane oxygenator (Maxima?, Medtronic Inc., Anaheim, CA92807 USA) and a pulsatile flow (Sarns? Inc/3M Ann Arbor, Michigan 48103 USA). When patient was on total CPB, the IPPV of lungs and isoflurane inhalation was stopped. Haematocrit value was kept about 25%. After aortic cross clamping, cold crystalloid cardioplegia (15 ml/kg) at 40C was infused in aortic root with a pressure infusor bag. If required, cardioplegia (7 ml/kg) was repeated at 20-min interval during the period of aortic cross clamping. The body was cooled to a core temperature of about 280C. After completion of the repair; the aortic cross clamp was removed. If ventricular fibrillation resulted, the heart was defibrillated. By active rewarming core temperature was gradually increased to about 37.50C.
During the rewarming period, the patients were randomly allocated into three groups of 25 each. Group I patients received an intravenous infusion of SNP which was titrated to keep the MAP between 50 to 80 mmHg to obtain maximum pump flows of 2.6 to 2.8 L/min/m2. Group II patients received isoflurane through vaporiser in gas circuit of CPB machine and dial concentration was adjusted to keep the MAP between 50 to 80 mmHg to a maximum pump flows of 2.6 to 2.8 L/min/m2. Group III patients received isoflurane (dial concentration 0.2% to 0.5%), and if required, infusion of SNP. The SNP infusion was started at the rate of 0.2?g/kg/min and subsequently, the infusion rate was titrated to maintain a MAP of 50-80 mm Hg. The decrease in SVR/MAP produced by SNP was countered by increasing the pump flows. If there was further decrease in MAP, SNP was discontinued and dopamine was started to maintain MAP between 50 to 80 mm Hg at a maximum pump flows of 2.6 to 2.8 L/min/m2. The requirement of dopamine in various groups was recorded.
Rewarming of the patients, on bypass, was done until the nasopharyngeal and rectal temperatures were attained to 37.50C and 370C, respectively. Once bleeding was controlled and heart rate (HR) of more than 90/min, CVP between 6 to 12 mm Hg, systolic arterial pressure (SAP) of more than 100 mm Hg with MAP of more than 60 mm Hg and urine output of more than 1 ml/kg/min were achieved, CPB was terminated. If required, additional volumes (blood, blood products or ringer lactate), inotropic support (dopamine, dobutamine or adrenaline) and diuretics (frusemide 20-40 mg) were administered. At the end of surgery sterile dressings of dissected legs were done and extremities were covered with woollen blankets to prevent the heat loss in ambient temperature. The nasopharyngeal, rectal and thumb-pulp temperatures were continuously recorded during intraoperative period and six hours thereafter. During the study, duration of aortic cross clamp, total CPB period, the rewarming time and interval between the termination of CPB and end of surgery were recorded. Rewarming time was taken as the interval between the start of rewarming and attainment of nasopharyngeal temperature of 37.50C for a period not less than five min. Peripheral rewarming was assessed on both the arms and hands, using a four stage scale: (1) cold, (2) warm but patchy, (3) warm homogeneous, and (4) very warm. The difference between nasopharyngeal and thumb-pulp temperatures was recorded at 15 min interval till 6 hours postoperatively. Afterdrop in nasopharyngeal or rectal temperatures below 350C or a difference of more than 2.50C after the termination of CPB was considered to be significant. Total dose of SNP infusion and total duration was calculated at the end of study. Almost all the patients were on dopamine and/or dobutamine infusions postoperatively but none of the patient was receiving a concentration of more than 7?g/kg/min of each drug. At the end of surgery, all patients were shifted to cardiac intensive care unit for overnight elective pulmonary ventilation and haemodynamic monitoring. Next morning, weaning from ventilator was tried and successful tracheal extubation were recorded.
The data recorded are presented as mean values with their standard deviations. Student’s t-test, Fisher’s exact test, chi-square test and ANOVA were used to test the statistical significance. The P <0.05 was considered as statistically significant.
The demographic data of patients were comparable among the groups [Table - 1]. There were no statistically significant difference among the groups regarding the duration of surgery, aortic cross clamp and bypass time, lowest drop in nasopharyngeal, rectal and thumb-pulp temperatures during the cooling and the time between the end of CPB and the end of surgery [Table - 2] & [Table - 3].
The total rewarming time in group III patients was significantly shorter (P <0.05) than group I and II. The afterdrop in nasopharyngeal and rectal temperatures was lesser in-group III than group I and II but the difference among the groups was not statistically significant. There was a significant correlation between rectal temperature and thumb pulp temperature and afterdrop among the groups.
During active rewarming on CPB, the mean value of the highest and the lowest MAP were 92 ± 8.7 mm Hg and 40 ± 7.5 mm Hg in group I, 88 ± 7.5 mm Hg and 45 ± 8.2 mm Hg in group II, and 76 ± 5.5 mm Hg and 55 ± 7.5 mm Hg in group III [Table - 4]. The gap between highest and lowest MAP was 52 mm Hg in group I, 43 mm Hg in group II, and 23 mm Hg in group III. The MAP in group III patients was significantly stable. The sudden increase in MAP higher than 90 mm Hg was recorded in eight patients in group I, seven patients in group II and one patient in group III. The sudden upward and downward fluctuations in MAP were significantly less in group III than group I and II patients. The group III patients had significantly better control of MAP than group I and II (P <0.001). During CPB significantly less number of patients of group III required inotropic/vasopressure support [Table - 4].
In the peripheral rewarming evaluation, 13 patients of group I, 14 patients of group II, and 16 patients of group III were homogeneously warm; and four patients each of group I and II and three patients of group III were very warm. Eight patients of group I, seven patients of group II and six patients of group III were warm but patchy. The four-scaled assessment of the rewarming of arms did not show significant statistical differences among the groups.
In cardiac intensive care unit, after overnight elective pulmonary ventilation, 22 (88%) patients of group I, 20 (80%) of group II and 23 (92%) patients of group III had successful tracheal extubation. Two patients of group I, three patients of group II and one patient of group III required re-exploration due to inadequate haemostasis and bleeding from the grafts and continued to receive ventilatory support for more than 24 hours. One patient of group I, two of group II and one of group III died with in first 12 hours of surgery due to myocardial infarction and ventricular arrhythmias refractory to the treatment. All the survivors, irrespective of groups, had adequate amnesia and none had recall of the intraoperative events.
During active rewarming the body temperature is restored to normothermic level by gradually increasing perfusion temperature via the heat exchanger. Time required for rewarming varies with arterial perfusate temperature, patient temperature, and systemic blood flow. Excessive heating of perfusate is not advisable for at least three reasons: possible denaturation of plasma proteins, possible cerebral hyperthermia, and because dissolved gas can condense into bubbles if the temperature gradient is too high. The perfusate temperature is usually kept 100C warmer than brain temperature. Another way to rewarming is to increase pump flow, thereby, increasing heat input. During moderate hypothermia the patient behaves as if vasoconstricted with increased systemic vascular resistance. In the situation, increasing pump flow may result in unacceptable increase in arterial pressure. Pharmacological vasodilatation allows an earlier increase in pump flows and delivery of warmed arterial blood to low flow beds, making the rewarming process more uniform. When rectal or bladder temperature approaches 300C to 320C, patient appear to rapidly vasodilate. This is probably due to decrease viscosity and relaxation of cold induced vasoconstriction with gradual warming. Increasing pump flow at this point serves several purposes including increased heat transfer, support of systemic arterial pressure and increased oxygen delivery in the phase of increased oxygen consumption.
The use of SNP infusion is customary at many cardiac centres to facilitate uniform active cooling and active rewarming on CPB. Sudden fall in arterial pressures with wide fluctuation is not uncommon leading to the use of vasoactive drugs. Recently, Tugrul et al have used isoflurane during active rewarming of body on CPB and demonstrated good haemodynamic stability with improved homogenous rewarming. The use of vasodilators (SNP or isoflurane) during active rewarming on CPB is a routine practice at authors’ institute. In the present study, a combination of isoflurane (0.2-0.5%) and low dose SNP infusion (<1.0 ?g/kg/min) has been used to study its effect on MAP in order to evaluate the haemodynamic stability obtained with different pharmacological regimens during the rewarming period. MAP is the most commonly affected variable during haemodynamic instability in the rewarming phase of CPB. Occasionally, MAP fluctuation may be due to obstacle in the arterial line, obstructive flow through aortic cannula or inappropriate venous return. However, such problems were carefully looked upon and ruled out.
We chose nasopharyngeal site to monitor the core temperature, as it is unlikely to be affected by local cooling in pericardial region. Oesophageal temperature is known to be affected due to local cooling with crushed ice. Intermediate thermal zone temperature was monitored using rectal probe. The disadvantages of rectal temperature monitoring are potential dislodgement of the probe and possible interaction with the faecal matter. Bladder temperature monitoring was not preferred as it is known to be affected with urinary flow and the temperature catheters are quite expensive. For the temperature monitoring of peripheral thermal zone, we chose thumb-pulp as in the absence of good peripheral perfusion distal phalanges temperature is most commonly affected.
The afterdrop in core temperature is reported to be most profound within the first 45 to 90 minutes of the post bypass period, hence, in the present study, the afterdrop was measured at approximately 90 minutes of termination of bypass. Because the time from the termination of CPB to the end of surgery showed significant correlation with afterdrop. These results support that the afterdrop increases with time after termination of bypass. Ramsay et al has shown that an afterdrop in core temperature is usually seen because of incomplete total body rewarming on CPB. This afterdrop in core temperature is attributed to the heat distribution from the warm core to cool periphery in the post bypass period. Noback and Tinker showed that with the use of high pump flows and SNP infusion afterdrop may be decreased from 2.60C to 1.50C, but not totally negated. Other studies, have reported an afterdrop of core temperature by 1.80C to 20C, in their patients. Our observations are comparable with the studies of Noback and Tinker and Tugrul et al who used SNP and isoflurane, respectively to allow maximum pump flows during rewarming on CPB. The combination of low dose isoflurane (0.2-0.5%) and SNP (0.2-1.0 ?g/Kg/min) administration during active rewarming on cardiopulmonary bypass provides uniform rewarming and is not significantly different to SNP or isoflurane alone. However, the combined use of SNP and isoflurane in low doses provide more stable haemodynamic conditions than SNP or isoflurane alone. The unwanted fluctuations and sudden drop in MAP are avoided; requirements for inotropes and vasopressures are decreased. The groups could not be blinded is the drawback of this study.
In conclusion, during active rewarming on cardiopulmonary bypass the combined use of isoflurane and sodium nitroprusside in low concentrations is not superior to either drug alone in terms of uniform rewarming of the body, however, it provides better haemodynamic stability during cardiopulmonary bypass with lesser requirements of inotropes/vasopressures.
The authors sincerely thank Dr. Soma Kaushik, our head of the department whose constant encouragement resulted in early completion of this study. We are also thankful to our perfusionists Mr SB Singh and Mr Abhaya Bapat for their immense help during cardiopulmonary bypass.
[Table - 1], [Table - 2], [Table - 3], [Table - 4]