Clinical And Basic Research On Monitoring And Efficacy Of Volume Therapy

Objective: Blood volume management of patient during perioperative period, especially optimized fluid therapy in anesthesia practice plays an important role in clinic surgery. Reasonable blood volume management can maintain effective circulatory blood volume and stable dynamics, ensure sufficient organ perfusion, and improve the recovery of patients from surgery. The monitoring of circulatory blood volume is a premise for optimizing fluid therapy. In the clinic, the noninvasive monitoring techniques with monitoring routine blood dynamics are most commonly used to evaluate the circulatory blood volume. In recent years, some new techniques monitoring cardiac function, such as transesophageal doppler (TED), thoracic electrical bioimpedance (TEB) and partical CO2 rebreathing cardiac output (RBCO) are used in blood volume therapy. But it is poor understood how about the sensitivity of common monitoring parameters in different techniques to the changes of circulatory blood volume.It is very important that choosing an optimized blood volume therapy in the tumorectomy patients with gastroenteric tumor in which body fluid lost and hypovolumic occur easily before and during surgery. Up to now, it is not reported that applying TED with the most sensitive monitoring parameters in blood dynamics to evaluate and choose the best blood volume therapy.It has been proved in clinic practice and research that effective blood volume treatment could maintain the stable circulatory function and keep homeostasis of internal environment. But the further study on the blood volume therapy is limited for some kind of researches cannot be carried out in human beings. Most animal researches on blood volume therapy were performed on acute hemorrhagic shock model that cannot effectively mimic the hypovolumic state in clinic. There is fundamental difference between acute hemorrhagic shock and hypovolumic state that most patients displayed in anesthesia and surgery. So, it is necessary to set up a hypovolumic animal model that to be used for the study of blood volume therapy.There are many different kinds of fluids to be used for blood volume therapy nowadays, such as most commonly used hetastarch, gelatine and blood products. More recently, hypertonic saline was reported to be use for fluid replacement. It is still not known which one is the best to be used in hypovolumic state.The present study aims at: (1) To evaluate sensitivity of hemodynamic monitoring indexes to blood volume variation during clinical anesthesia; (2) To observe the effects of different fluid therapy in the patients with gastrointestinal tumorectomy; (3) To set up a hypovolumic animal model; (4) To explore the effects of fluid volume therapy on hypovolumic rabbit and the underlying mechanism.Methods:Part 1. Evaluation of hemodynamic indexes sensitive to the blood volumeForty male patients with liver cancer, aged from 40 to 50 yrs, no cardio-pulmonary disturbance (ASAâ… o râ…¡), were chose in the study. 6% hydroxyethyl statch (HES130/0.4) was given i.v in 5 series of stage, that is 2ml·kg^-1, 4ml·kg^-1, 6ml·kg^-1, 8ml·kg^-1 and 10ml·kg^-1,with speed of 0.67 ml·kg^-1·min^-1. Central venous pressure (CVP) was recorded through cannulation. Three kinds of noninvasive cardiac function monitoring techniques were used to evaluate the sensitivity of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean artery blood pressure (MAP), heart rate (HR), calculated left ventricular ejection time (LVETc), cardiac output (CO), stroke volume (SV), cardiac index (CI), stroke volume index (SI), and systemic vascular resistance (SVR) to blood valume variation.Part 2. The effects of different fluid therapy in the patients with gastrointestinal tumorectomyThirty-six adult male and twenty-four adult female patients with gastroentestine cancer, no cardio-pulmonary disturbance (ASAâ… orâ…¡), were chose in the study. The patients were divided into three groups: Standard fluid replacement group (SFR), acute hypervolemic hemodilution group (AHH) and goal-directed fluid replacement group (GFR). Different fluids were given to the patients according to groups. The cardiac functional indexes, LVETc,CVP,CO,SV,CI ,SI ,MAP,HR were recorded at the time patient entered into operative room, after anesthesia induction, at starting time of operation, at different time point during the operation and at end of operation, respectively. Oxygen metabolism was evaluated after anesthesia induction and at end of operation. The amount ofβ2-microglobulin (β2-MG) and lactic acid(LD)was examined when patients entering the operation room and the end of operation, respectively. Total amount of patient urine during operation was collected.Part 3. Setting up of a hypovolumic animal modelForty adult male New Zealand white rabbits were randomly divided into five groups: Control group (Con), 20% blood losing group (20-BL), 25% blood losing group (25-BL), 30% blood losing group (30-BL) and shock group (Shock). Animals in Shock were treated with bloodletting quickly through femoral artery to decrease MAP to 40mmHg that persisting for one hour. Animals in blood losing groups were treated with bloodletting slowly through femoral vein to losing demanded amount of blood in 30-40 minutes. Animals in Con were treated with surgery operation, no blood losing. ECG in leadâ…¡, left ventricular systolic pressure(LVSP), left ventricular end diastolic pressure(LVEDP), positive and negative maximal differentials of LVSP(+LVdp/dtmax,-LVdp/dtmax), CVP, MAP and HR were monitored continuously during experiment. Blood flow speed and diameter of capillary in mesentery were measured at times before blood losing, after blood losing and 30 min after blood losing, respectively. Blood gas analysis was made using blood from femoral arterial and central vein.At end of experiment, tissue sample were taken from heart and intestine to observe the ultrastructural organization under the light and electronic microscopes. Part 4. The effects of fluid volume therapy on hypovolumic state rabbit and the underlying mechanism.Thirty two male adult New Zealand white rabbits in hypovolumic state were randomly divided into four groups: Stand group (S), 6% hetastarch group (V), autoblood group (B) and hypertonic solutions (H). Animals were treated with i.v different solutions, routine 0.9% saline solution in S group, a mixture solution of crystal and colloid, autoblood in B group, and a 7.5% hypertonic saline solution in H group. Monitoring indexes of blood dynamic and cardiac function were recorded at different times during experiment.β₂-microglobulin, lactic acid and ANGâ…¡in blood were measured, and blood gas analysis was made. Blood flow speed, diameter of capillary and the situation of blood cells were recorded. Heart and intestine sample were taken at end of experiment for observing the ultrastructural organization.Results:Part 1. Evaluation of hemodynamic indexes sensitive to the blood volume1.Cardiac function varied differently in different stage of infusion (P<0.05). In 2ml·kg-1 stage, LVETc increased; in 4ml·kg-1 stage, SV,SI,CVP increased; in 6ml·kg-1 stage, CO,CI increase and SVR decreased; in 8ml·kg-1 stage, SBP,DBP,MAP increased and HR decreased.2.There was no significant different between the indexes from three noninvasive cardiac function monitoring techniques. The correlation coefficient (rs) of LVETc, CVP, CO, SV, CI, SI, SVR, SBP, DBP, MAP, HR to fluid amount were 0.98±0.01, 0.90±0.02,0.80±0.04,0.81±0.02, 0.79±0.02,0.78±0.02,-0.21±0.04,0.20±0.04,0.15±0.04,0.18±0.03,-0.11±0.02, respectively.3.The rs of LVETc was significant higher than that of CVP,CO,SV,CI,SI(P<0.05),rs of CVP was significant higher than that of CO,SV,CI,SI (P<0.05)。Part 2. The effects of different fluid therapy in the patients with gastrointestinal tumorectomy1. Effects of different fluid therapy on hemodynamics The LVETc of patients in three groups after anesthesia induction was decreased below 350ms. The LVETc recovery time to 350ms during solution replacement in SFR, AHH and GFR was 75±17 min, 19±4 min and 22±3 min,respectively. The recovery time in SFR was significantly longer than that in AHH and GFR (P<0.05). The ratio of total duration of LVETc longer than 400ms to total operative time in SFR, AHH and GFR was 0.054±0.003%, 0.035±0.004% and 28.142±3.021%,respectively. The ratio in AHH was significant bigger than that in AHH and GFR (P<0.05). The ratio of duration of LVETc shorter than 350ms to total operative time in SFR, AHH and GFR was 40.768±3.155%, 9.130±1.586% and 8.344±1.220%,respectively. The ratio in SFR was significant bigger than that in AHH and GFR (P<0.05).There was no different of CVP between three groups after anesthesia induction. CVP in GFR during the period of operation starting to 60 min operation was significant lower than that in AHH (P<0.05), and CVP in GFR during the period of 40 to 60 min operation was significant higher than that in SFR (P<0.05).Incidence of bad event of hemodynamics in SFR, AHH and GFR was 2.40±1.31/per cases, 0.08±0.04/per cases and 0.11±0.03/per cases. The value in SFR was significant higher than that in AHH and GFR (P<0.05). And the amount of urine in AHH and GFR was significant greater than that in SFR (P<0.05).2. The Effects of different fluid therapy onβ2-MG and LDβ₂-MG and LD in GFR and AHH were not changed at the end of operation compared with the time of patient entering the operative room, butβ₂-MG and LD in SFR were significant increased at end of the operation (P<0.05).Part 3. Setting up of a hypovolumic animal model1.The effects of hypovolumic state on blood pressure Compared with Con, CVP and MBP of animals after blood losing were significant decreased in a volume-dependent manner (P<0.05). MBP and CVP decreased 6.4% 14.5% in 20-BL,15.7% and 15.1% in 25-BL, 22.6% and 28.4% in 30-BL, 50% and 51.8% in Shock. CVP and MBP in 25-BL, 30-BL and Shock were decreased significantly (P<0.05) compared with Con. CVP and MBP in Shock were decreased significantly (P<0.05) compared with 30-BL.At 30minuts after blood losing, MBP and CVP in 20-BL and 25-BL totally recovered. MBP and CVP could not return to normal in 30-BL and did not recover in Shock (P<0.05).2. The effects of hypovolumic state on cardiac functionCompared with Con, indexes of cardiac function after blood losing changed significantly in a volume-dependent manner (P<0.05). The more blood losing the severer the indexes of cardiac function changed. LVSP, +LVdp/dtmax and -LVdp/dtmax decreased 13.8%, 11.0% and 13.5%, and LVEDP increased 13.3% in 20-BL, respectively; decreased 13.9%, 13.3% and 13.5%, and increased 17.1% in 25-BL, respectively; decreased 28.6%, 33.5% and 36.3%, and increased 43% in 30-BL, respectively; decreased 80.3%, 97.2% and 96.3%, and increased 243% in Shock, respectively.At 30minuts after blood losing, the cardiac function indexes in 20-BL and 25-BL totally recovered. The indexes could not return to normal in 30-BL and did not recover in Shock (P<0.05).After blood losing, HR in Shock animals decreased significantly and showed obvious myocardial ischemia.3. The effects of hypovolumic state on red blood cell and oxygen metabolism Hematocrit (Hct) in 20-BL, 25-BL, 30-BL and Shock decreased 2.5%, 3.07%, 3.21 and 6.7% after blood losing compared with Con (P<0.05), respectively. Oxygen delivery (DO₂) in 20-BL was increased and both DO₂ and oxygen consumption (VO₂) in 25-BL were increased (P<0.05). VO2 and oxygen extract rate (ERO₂) in Shock decreased after blood losing (P<0.05).4. The effects of hypovolumic state on morphology of heart and small intestineCompared with Con, animals in 20-BL and 25-BL showed an unclear transverse striation of myocardium and small bleeding in the capillary between muscles under the light microscope, and small parts of myocomma fusion or disappeared under the electronic microscope. Animals in 30-BL showed small focal degeneration of cardiomyocytes under the light microscope and edema around nuclear as well as small parts fusion of crista or membrane in mitochondrial under the electronic microscope. Animals in Shock showed diffusing necrosis in myocardium and severe bleeding in the capillary between muscles under the light microscope, and obvious edema around nuclear, big parts fusion or disappear of crista or membrane of mitochondria, and clear cavitation in mitochondria under the electronic microscope.Compared with Con, small intestine of animals in 20-BL and 25-BL shows low-grade infiltration of inflammatory cells and congestion. Animals in 30-BL showed villus edema and middle-grade inflammatory cells infiltration. Animals in Shock showed magnified interstitial edema in villus, severe-grade inflammatory cells infiltration and congestion.5. The effects of hypovolumic state on microcirculation of small intestinal mesenteryThere were no obviously changes of microvessel diameter and blood flow speed in 20-BL animals after blood losing. After blood losing, animals in 25-BL showed that microvessel contracted and blood flow speed in artery slowed, animals in 30-BL showed that microvessel contracted and blood flow speed in both artery and vein slowed significantly (P<0.05). At the 30min after blood losing, microvessel diameter and flow speed recovered to normal in 25-BL animals, but did not recovery in 30-BL animals. There was partial occlusion around the capillary network in 30-BL animals. Animals in Shock showed that microvessel dilated and blood flow speed decreased obviously after blood losing and 30min after blood losing. Also significant blood stasis, erythrocyte aggregation and/or blood plasma column, and hemorrhage, exudation, leucocytes attach around vessel could be observed.Part 4. The effects of fluid volume therapy on hypovolumic rabbit and the underlying mechanism 1.The effects of fluid volume therapy on blood dynamic and cardiac functionCVP, MAP and cardiac indexes in S animals were kept at same low level as stage of blood losing. All the indexes in V, B and H animals returned to normal after fluid replacement (P>0.05), but 30 minutes after fluid replacement the indexes in H animals lowed down to the low level of blood losing (P<0.05). HR and ECG in each groups had no significant change during the experiment.2. The effects of fluid volume therapy on microcirculation of small intestine mesenteryCompared with normal state, the diameter of microvessel decreased and blood flow speed slowed after blood losing in all animals (P<0.05). In H group, the microcirculation was returned to normal after fluid replacement, but 30min after fluid replacement the diameter of arteriole decreased and flow speed slowed down with pendulum-like flow or stasis, red blood cell aggregation, white blood cell attachment on vessel and exudation were showed. In S group, the diameter of arteriole contracted with flow speed no change, the diameter of veinule dilated with flow speed slow after fluid replacement (P<0.05). In B group, microcirculation returned back to normal after fluid replacement, but with partial vessel occlusion in capillary network.In V group, microcirculation recovered to normal after fluid replacement and collateral circulation appeared in the capillary network that is not exists in normal condition.3. The effects of fluid volume therapy on morphology of heart and intestineAfter blood losing, all animals showed unclear transverse striation of myocardial fiber, small bleeding in capillary between muscles, small focal degeneration of cardiomyocytes under the light microscope, and edema around nuclear as well as small parts fusion or disappear of crista or membrane of mitochondria under the electronic microscope. After fluid replacement, animals in S, H and B group showed different grade of congestion between muscles under the light microscope, and different grade of edema around nucleus under the electronic microscope. Animals in H group showed unclear transverse striation of myocardial fiber and pyknosis in some mitochondria. Cardiac tissue in V group looked like normal tissue under both light and electronic microscope.Small intestine of all animals showed villus edema, middle-degree inflammation cells infiltration and congestion after blood losing. After fluid replacement, the changes described above were aggravated in exaggated in H group and was lessened in S and B groups. Small intestinal tissue in V group looked like normal tissue.4. The effects of fluid volume therapy on blood rheologyCompared with normal condition, the reduced viscosity and the index of RBC aggregation under low-shear and high-shear speeds in S, V and B groups at 30 min after fluid replacement were reduced (P<0.05). The ragidity index and aggregation index of RBC was increased in H group (P<0.05).5. The effects of fluid volume therapy onβ₂-MG, Ld and AngⅡβ₂-MG and Angâ…¡in each group were increased after blood losing (P<0.05) and recovered after fluid replacement. After 30 minutes fluid replacement,β2-MG, LD and Angâ…¡in H group were increased significantly (P<0.05).6. The effects of fluid volume therapy on oxygen metabolism DO₂ and VO₂ in each group were increased (P<0.05) after blood losing, but ERO2 did not change (P>0.05). DO₂, VO₂ and ERO₂ in all groups were increased again after fluid replacement (P<0.05) and recovered only in H group at the time 30min after fluid replacement (P<0.05).Conclusion:1 The sensitivity of LVETc,CVP to blood volume variation are the highest and both of them are the best indexes to evaluating blood volumic therapy in clinic.2 The goal-directed fluid replacement has the best result of volume treatment, improving effective circulation blood volume, maintaining the stable of hemodynamics and guanranting sufficient organ perfusion and oxidation in gastrointestinal cacer patients during the operation. 3 The hypovolumic rabbit model with 30% blood losing of the body was different essentially from the acute shock rabbit model and can simulate well the hypovolumic state of anesthesia patients clinically.4 6% hetastarch solution(HES, 130/0.4)has a best effect of fluid volume expansion, correcting circulating blood volume, improving microcirculation and organ perfusion effectively, which is related with the decreasing of blood viscosity, the speeding of blood flow velocity and the decreasing of Angâ…¡in blood.