Anesth Analg 2003;97:972-978
© 2003 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
The Hemodynamic and Metabolic Effects of Shivering During Acute Normovolemic Hemodilution
Valéria Perez-de-Sá, MD PhD, DEAA*,
Doris Cunha-Goncalves, MD DEAA
,
Henning Schou, MD PhD
,
Christer Jonmarker, MD PhD, DEAA
, and
Olof Werner, MD PhD, DEAA*
*Children’s Hospital, the
Heart Lung Division, and the
Department of Anesthesia and Intensive Care at the University Hospital, Lund, Sweden, and from
Children’s Hospital and Regional Medical Center, The University of Washington, Seattle, Washington
Address correspondence to Valéria Perez de Sá, MD, PhD, Department of Pediatric Anesthesia and Intensive Care, Children’s Hospital, University Hospital of Lund, Lund, SE-221 85, Sweden. Address email to Valeria.Sa{at}anest.lu.se
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Abstract
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To assess the hemodynamic and metabolic effects of shivering during extreme normovolemic hemodilution, we anesthetized 16 pigs with fentanyl-midazolam-pancuronium. Mild hypothermia (36.5° ± 0.1°C) was induced by surface cooling, and the animals were randomized to either a control group (hemoglobin 118 ± 3 g/L) or a hemodilution group (hemoglobin 52 ± 2 g/L). In the latter group, blood was replaced with an isotonic Ringer’s acetate/dextran 70 solution. Shivering was allowed to occur by a controlled decrease in the infusion rate of pancuronium. Shivering increased oxygen consumption (
O2) in both groups (P < 0.001). Initially, this was predominantly compensated for by an increased oxygen extraction ratio (ER), but when O2 was 2.3 ± 0.2 times baseline, critical levels of mixed venous oxygenation (S
O2 = 18% ± 2%; PO2 = 22.5 ± 1.5 mm Hg) and ER (82% ± 3%) were recorded in anemic animals. Control animals did not reach critical levels until O2 was maximal (3.7 ± 0.3 times baseline). Maximal attained O2 was less (2.9 ± 0.1 times baseline) in the anemic animals (P = 0.01), and at this stage two of these pigs had myocardial lactate production, one of which died in ventricular fibrillation. Coronary perfusion pressure was significantly less (P < 0.001) in the anemic animals. We conclude that in this experimental model, maximal shivering as measured by O2 was limited in hemodiluted animals, and left ventricular oxygen balance was marginal, as evidenced by a decreased lactate uptake and extraction.
IMPLICATIONS: The effect of acute increases in oxygen consumption (shivering) on severely anemic individuals has not been evaluated. In this experimental model, left ventricular oxygen balance was marginal, as evidenced by decreased lactate extraction.
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Introduction
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In the last two decades, both medical and lay communities have become more aware of the risks associated with homologous blood transfusions (1). Although blood transfusion in developed countries has never been safer, the fear remains for infection by known and unknown organisms and for other side effects, such as immunological reactions or compromised immunocompetence (1). During operative blood loss, these risks need to be balanced against the hazards of anemia itself (2,3). Some factors, such as age and the presence of cardiovascular disease, are recognized to decrease tolerance to anemia. Young healthy individuals can withstand hemoglobin concentrations less than 70 g/L (4), whereas older patients with atherosclerosis may be at increased risk for myocardial hypoxia when hemoglobin (Hgb) decreases to less than 100 g/L (5).
Core hypothermia increases the incidence of myocardial ischemia (6). Postoperative shivering is a frequent complication of inadvertent perioperative hypothermia, and although commonly associated with 200%–300% increases in oxygen consumption (7) and marked hemodynamic changes, a direct relation between shivering and significant morbidity/mortality has not been established. Nevertheless, our own clinical observations indicate that shivering may be dangerous when there is a limited oxygen carrying capacity. In a previous study in children undergoing bone marrow harvesting with restricted use of allogeneic blood transfusions, the only complication observed was an episode of arterial desaturation in a patient who shivered during the immediate postoperative period (8).
The aim of the present study was to investigate, in an experimental pig model, the metabolic and hemodynamic consequences of shivering during extreme, acute, normovolemic hemodilution by evaluating global oxygenation indexes as well as left ventricular oxygenation and lactate extraction. We hypothesized that severely anemic animals would be more vulnerable than those with normal Hgb to the negative effects of shivering.
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Methods
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After approval by the local Ethical Committee on Animal Research, 16 Swedish Landrace piglets of either sex weighing 20–25 kg were premedicated IM with 15 mg midazolam and 0.5 mg atropine. Anesthesia was induced with 2 mg/kg IV ketamine chloride. After local anesthesia with 2% lidocaine, a cuffed endotracheal tube was inserted through a tracheotomy. Initiation of mechanical ventilation (Servo 900 B, Siemens-Elema AB, Solna, Sweden) was facilitated by IV injections of 20 µg/kg fentanyl, 0.3 mg/kg midazolam, and 0.3 mg/kg pancuronium. Anesthesia was then maintained with continuous infusions of the same drugs as follows: 20 µg · kg-1 · h-1 fentanyl, 0.3 mg · kg-1 · h-1 midazolam, and 0.3 mg · kg-1 · h-1 pancuronium. The ventilator was initially set to deliver an air/oxygen mixture (FIO2, 0.5) at a tidal volume of 10 mL · kg-1 · min-1, a rate of 10 breaths/min, and 5 cm H2O of positive end-expiratory pressure. Tidal volume was thereafter unchanged, but ventilatory rate was continuously adjusted to maintain normocapnia (PaCO2, 34–38 mm Hg as measured in the blood/gas machine at 37°C). Maintenance of a stable PaCO2 despite the rapid changes in metabolic rate that occurred during the experiment was simplified by monitoring ETCO2 and CO2 production (CO2) with a mainstream capnometer (930; Siemens-Elema AB). A maintenance infusion of glucose and electrolytes (Ringer-Glucose®: Na+ 73.5 mmol, K+ 2 mmol, Ca+2 1.15 mmol, Cl- 77.8 mmol, glucose 25 g, Pharmacia-Upjohn, Uppsala, Sweden) was given at 5 mL · kg-1 · h-1 throughout the study.
An arterial catheter was placed in the left carotid artery and advanced into the aorta for measuring mean arterial blood pressure (MAP) and withdrawing blood. An 8F introducer was placed in the right atrium via direct puncture of the cranial caval vein. A thermodilution catheter (Optometrix, Abbott Laboratories, North Chicago, IL) was inserted through the introducer into the right pulmonary artery for measuring pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), mixed venous oxygen saturation (SO2), cardiac output (CO), and temperature, and for sampling of mixed venous blood. Central venous pressure (CVP) was monitored from a side port of the introducer. A 5F thermistor catheter (Webster Laboratories, Baldwin Park, CA) was inserted through the right external jugular vein into the coronary sinus, and its tip was advanced into the great cardiac vein (GCV) 3 cm beyond its confluence with the hemiazygous vein for sampling blood draining the bulk of the left ventricle. Correct positioning and adequate mixing were confirmed by injection of radio-opaque contrast during fluoroscopy and by withdrawal of blood with an oxygen saturation of approximately 25%.
Oxygen consumption (O2) was monitored by indirect calorimetry (Deltatrac; Datex Inc, Helsinki, Finland). The instrument was warmed for 30 min and calibrated as recommended by the manufacturer. The calorimeter was used only to guide the experiment, i.e., to indicate when the desired level of O2 had been reached and to stabilize metabolism around that level during measurements. During the preparation, core (pulmonary arterial) temperature was kept at 38°–39°C with the help of heating pads and a reflecting blanket.
Intravascular catheters were connected to disposable electronic pressure transducers (Codan Triplus AB, Stockholm, Sweden) balanced to atmospheric pressure and with reference zero placed at the midthoracic level. Electrocardiogram and pressures were displayed and simultaneously recorded on an inkjet recorder (Mingograph 7; Siemens-Elema AB). CO was determined by thermodilution. The measurements were done at end-expiration using 10 mL of room temperate saline, and the mean value of 3 measurements within ±10% variation of each other was recorded. Vascular resistances were calculated from standard formulas. The rate-pressure product (RPP) was calculated as the product of heart rate (HR) x systolic arterial blood pressure. Coronary perfusion pressure (CPP) was calculated as the difference between diastolic arterial blood pressure and PCWP.
Blood gas tensions, pH, base excess, bicarbonate concentration, and electrolytes (Na+, K+, and Ca2+) were measured with an ABL 510 autoanalyzer (Radiometer Medical A/S, Copenhagen, Denmark). Hgb concentration and oxygen saturation were determined with an OSM 3 hemoximeter (Radiometer Medical A/S) integrated with the ABL 510 with internal correction for swine Hgb absorption characteristics. Blood gas tensions were not corrected for temperature. All values are reported at 37°C. Whole-body oxygen delivery and consumption was calculated from arterial (CaO2) and venous oxygen content (CO2), and CO according to standard formulas. Whole body ER was calculated as the ratio between (CaO2 -CO2) and CaO2. Left ventricular ER (ERLV ) was calculated as the ratio between (CaO2 - CGCVO2) and CaO2, where CGCVO2 is the oxygen content of the blood obtained from the GCV. Arterial and GCV blood samples were simultaneously drawn to measure lactate concentration by a spectrophotometric method (EktaChem 700 XR-C, Eastman Kodak Company, Rochester, NY). Left ventricular lactate difference was calculated as LGCV - Lart, where LGCV is the GCV lactate concentration and Lart is the arterial lactate concentration. Negative values indicate lactate extraction by the myocardium and, consequently, positive values indicate lactate production.
After surgical preparation, 30 min were allowed before the first set of measurements was obtained (stage 1, baseline). Central temperature, as measured by the pulmonary artery catheter thermistor, was then reduced to 36° ± 0.5°C by surface cooling (Fig. 1). After 15 min stabilization at the target temperature, stage 2 (mild hypothermia) measurements were obtained. At that point, all animals received 0.3 mL/kg IV of dextran-hapten (Promiten®; Pharmalink, Spånga, Sweden), to prevent anaphylactoid reactions to dextran. The animals were then randomly assigned to one of two groups: control or hemodilution. In the latter, blood was withdrawn at a rate of 50 mL/min, and simultaneously replaced with the same amount of a warm (36°C) crystalloid/colloid solution that was obtained by mixing equal volumes of 6% dextran-70 (Macrodex®; Pharmalink, Spånga, Sweden) and Ringer’s acetate solution (Ringer-Acetat®; Baxter, Kista, Sweden). Each liter of the final solution contained dextran-70 30.0 g, Na+ 142 mmol, K+ 2 mmol, Ca2+ 1 mmol, Mg++ 0.5 mmol, Cl- 132 mmol, and acetate 30 mmol. Blood gas analyses and hematocrit were checked after every 500 mL of volume exchange. When the target Hgb concentration (50 g/L) had been reached, 30 min were allowed for stabilization before new measurements were taken (stage 3, hemodilution). The hemodilution process took 71 ± 7 min, and control animals were left undisturbed for approximately the same time period (63 ± 6 min) to decrease the likelihood of time-related bias.
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Figure 1. Data are presented as mean ± SE. Significance of differences between groups is indicated by: *(P < 0.05) and (P < 0.01), respectively. Significance of differences within groups is indicated by letter symbols, as follows. A = P < 0.05, a = P < 0.01, when comparing stages 2 versus 1, 3 versus 2, and 6 versus 1 (paired Student’s t-test). B, b, C, and c refer to findings during progressive shivering (2 x O2: Max O2) after correcting for multiple comparisons (Student-Newman-Keuls test): B = P < 0.05, b = P < 0.01, for stage 4 versus 3 and 5 versus 3; C = P < 0.05, c = P < 0.01, for stage 5 versus 4.
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The pancuronium infusion was turned off to allow shivering to occur, and, because surface cooling and shivering produces a strong sympathetic stimulation (9), the fentanyl and midazolam infusions were increased by 20% to ensure an adequate anesthetic depth.
When perceptible shivering and/or an increase in O2 were observed, the animals were given a small bolus of pancuronium (0.02 mg/kg) and the infusion was restarted at a rate of 0.1 mg · kg-1 · h-1 (one-third of the initial rate). The pancuronium infusion was then decreased by 20% every 15 min to obtain a slow increase in muscle activity and O2. The next set of measurements (stage 4) was obtained at a O2 that was approximately 2 times more than baseline, as indicated by the indirect calorimeter.
During stage 4, repeated minute boluses of pancuronium 10 µg (approximately 0.5 µg/kg) were administered to maintain O2 and thus, presumably, shivering stable for 
10 min so that measurements could be obtained under steady state conditions. To produce maximal shivering (stage 5), defined as the maximal observed O2, the pancuronium infusion was turned off while surface cooling was continued. New measurements were obtained 30 min later (pilot experiments indicated that there would be no further increase in O2 beyond this point). Finally, a new bolus of pancuronium (0.1 mg/kg) was given, and the pancuronium infusion restarted to abolish shivering, after which central temperature was stabilized at 38° ± 0.5°C. A final set of measurements (stage 6) was obtained 15 min later.
SigmaStat 2.0 (Jandel Scientific Software, Erkrath, Germany) was used for statistical analysis. Data were analyzed by two-way repeated-measures analysis of variance (ANOVA) for one factor to avoid spurious significance resulting from multiple testing. If ANOVA indicated significant overall differences, further within-group analysis was done with the paired Student’s t-test for stages 2 versus 1 (to assess the effect of mild hypothermia), 3 versus 2 (to assess the effect of hemodilution during hypothermia); and 6 versus 1 (to assess the stability of the preparation, just in the control group). The all pairwise multiple comparison Student-Newman-Keuls method was used to isolate which stages were different from each other with progressively increasing O2 (stages 3, 4, and 5). The unpaired Student’s t-test (normally distributed data) or the Mann-Whitney U-test was used to identify at which stages there was a significant difference between groups when indicated by ANOVA. P values <0.05 were considered significant. Data are given as mean ± SEM.
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Results
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The study lasted 416 ± 36 min in the control group and 443 ± 18 min in the hemodilution group (not statistically significant). There were no differences between the two groups during stages 1 and 2. Hemodilution elicited the expected hemodynamic changes: DO2 decreased because of the 60% decrease in Hgb that was not fully compensated for by a corresponding increase in cardiac index (CO/weight) (CI), but O2 was maintained by increasing ER. MAP and systemic vascular resistance index (SVR/weight) (SVRI) were significantly lower in the anemic group (Table 1).
During stage 4, when O2 was 2.0 ± 0.2 and 2.3 ± 0.2 times that of baseline for control and anemic animals respectively (Fig. 2), ER increased to meet the increased oxygen demand and SO2 and PO2 decreased in both groups (Fig. 3). HR decreased and filling pressures and stroke volume index (CI/HR) (SVI) increased, but CI increased only in anemic animals (Table 1). ERLV increased only in the anemic group, whereas LGCV - Lart increased in both. Left ventricular (LV) lactate extraction (LVLE = [Lart - LGCV/Lart] x 100) was less in anemic than in control animals (P = 0.009) (Table 2). Unlike the control animals, anemic animals showed the nadirs for SO2, SGCVO2, and PGCVO2 and maximal ER already at this stage.
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Figure 2. Data are presented as mean ± SE. DO2 = systemic oxygen delivery; O2 = systemic oxygen consumption. Significance of differences between groups is indicated by: *(P < 0.05) and (P < 0.01), respectively. Significance of differences within groups is indicated by letter symbols, as follows. A = P < 0.05, a = P < 0.01, when comparing stages 2 versus 1, 3 versus 2, and 6 versus 1 (paired Student’s t-test). B, b, C, and c refer to findings during progressive shivering (2 x O2: Max O2) after correcting for multiple comparisons (Student-Newman-Keuls test): B = P < 0.05, b = P < 0.01, for stage 4 versus 3 and 5 versus 3; C = P < 0.05, c = P < 0.01, for stage 5 versus 4.
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Figure 3. Data are presented as mean ± SE SO2 = mixed venous oxygen saturation; PO2 = mixed venous partial pressure of oxygen. Significance of differences between groups is indicated by *(P < 0.05) and (P < 0.01), respectively. Significance of differences within groups is indicated by letter symbols, as follows: A = P < 0.05; a = P < 0.01; when comparing stages 2 versus 1, 3 versus 2, and 6 versus 1 (paired Student’s t-test). B, b, C, and c refer to findings during progressive shivering (2 x O2: Max O2) after correcting for multiple comparisons (Student-Newman-Keuls test): B = P < 0.05, b = P < 0.01, for stage 4 versus 3 and 5 versus 3; C = P < 0.05, c = P < 0.01, for stage 5 versus 4.
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During maximal O2 (stage 5, maximal shivering), surface cooling was insufficient to maintain body temperature unchanged, and the temperature increased (Fig. 1). Despite an increase in CI by 60% in relation to stage 3 in the control group, ER increased markedly, and SO2 and PO2 reached a nadir in face of the nearly 300% increase in O2. Although maximal O2 was less in anemic animals than in controls (2.9 ± 0.1 versus 3.7 ± 0.3, respectively) (P = 0.01), unlike the control group, in which Lart decreased to preshivering levels, Lart was still higher than stage at 3 in the anemic group, but neither Lart (Table 1) nor pH or arterial base excess differed significantly between groups.
LV hypoxia, as indicated by lactate production (positive LGCV - Lart difference), was observed in two anemic animals, and LVLE was significantly lower than in the control group. One of these two animals developed cardiac failure and died in ventricular fibrillation. Although RPP was not different between groups, CPP was significantly higher in the control group from stage 3 through the end of the experiment.
The relation between O2 and DO2 is illustrated in Figure 2. During stage 3, control animals had a considerable "oxygen transport reserve" as assessed by the DO2 - O2 difference of 18.9 ± 1.4 mL · kg-1 · min-1, and a DO2/O2 ratio of 3.82 ± 0.2. During maximal shivering (stage 5), the corresponding values were 9.6 ± 1.6 mL · kg-1 · min-1 and 1.33 ± 0.04, respectively.
In contrast, hemodilution decreased DO2 - O2 from 18.3 ± 1.2 to 6.9 ± 0.8 mL · kg-1 · min-1 and DO2/O2 from 3.7 ± 0.2 to 2.1 ± 0.1. During shivering (stages 5), DO2 was close to O2, the difference being only 3.5 ± 0.5 mL · kg-1 · min-1 and the DO2/O2 ratio was 1.18 ± 0.01.
To assess the stability of the preparation, we compared the first (baseline) and last (stage 6) measurements in the control group. During stage 6 (normothermia restored, muscle relaxation, no shivering), the animals had a smaller Hgb value than during stage 1 (98 versus 112 g/L, P < 0.001), a lower SVRI (P = 0.003), and higher CI (P < 0.001) than during stage 1. Direct comparison between stages 1 and 6 was not meaningful in the hemodilution group, but similar changes probably occurred, as indicated by the decrease in Hgb from 52 to 46 g/L between stage 3 (posthemodilution, hypothermia) and stage 6.
Except for the finding that SGCVO2 was greater in hemodiluted animals (P < 0.001), and ERLV and LVLE lower (P < 0.001 and P = 0.003, respectively), comparison between groups during stage 6 indicated results consistent with those obtained during stage 3.
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Discussion
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The major findings of this study were that anemic animals withstood shivering well, but were unable to fully compensate for the increased oxygen demand imposed by shivering, as evidenced by decreased LV lactate extraction already at stage 4 (O2 twice baseline) and lower CPP. Furthermore, during stage 5 (maximal O2), two anemic animals developed myocardial lactate production and one of these animals died. The second major finding of this study was that maximal oxygen consumption induced by shivering was limited by acute normovolemic anemia.
The experimental model allowed rather close control of the degree of shivering as reflected by O2 and may therefore be useful in other study designs. It should be noted, however, that although the gradual increase in O2 is analogous to that seen during a treadmill exercise test, similar hemodynamic responses might not be elicited. The uncoordinated involuntary skeletal muscle activity of shivering, in which all energy released by contractions appears as heat (10), is different from the coordinated muscle activity of treadmill exercise. Also, our model involves mechanical ventilation, which removes the work of breathing and ensures adequate ventilation but restricts venous return. Comparison of our findings with those obtained during treadmill exercise seems to confirm that these two methods of increasing O2 result in different hemodynamic responses. During treadmill testing, healthy individuals (both humans and swine) exhibit a moderate increase in MAP because the increase in CO dominates over the vasodilation occurring in working skeletal muscle (11,12). In our study, however, MAP generally decreased with increasing muscle activity, possibly because the generalized nature of muscle activity during shivering results in lower SVR when compared with treadmill exercise at equivalent levels of O2.
An unanticipated finding was that shivering was first associated with an increase, and then a decrease, in Lart. This was observed in both groups but was most noticeable in the control group (Table 2; stage 4). The explanation may be that the temperature changed; the animals were hypothermic during stage 4 but became normothermic during stage 5 because we were unable to prevent the core temperature from increasing despite continued intense surface cooling. Temperature markedly influences metabolism in skeletal muscle (12). Thus, cooled, exercising muscle exhibits increased glycolysis and decreased lactate removal (12). Lactate removal by the liver also decreases during hypothermia (13). In exercising untrained men, Lart does not increase until O2 is approximately four times the resting value (14), so it is unlikely that the doubling of O2 at stage 4 in comparison with baseline by itself explains the increase in blood lactate, at least not in the control group.
The animals were exposed to a degree of hemodilution (corresponding to a 50% reduction in oxygen carrying capacity of the blood) that is comparable to levels accepted in clinical practice in some centers (15). The hemodynamic and metabolic changes after hemodilution are in accordance with those observed by Trouwborst et al. (16). Although the PO2 at stage 3 was close to the critical value for supply-dependent O2 observed by these authors in normothermic hemodiluted pigs (16), there were no signs of anaerobic metabolism in any of our animals at this stage.
Also, the increase in O2 during shivering was similar to that found in postoperative patients. Dupuis et al. (17) reported increases in O2 ranging from two to four times the baseline values in patients shivering after coronary bypass surgery.
In hemodilution animals, signs of myocardial ischemia were first noticed during stage 5 when O2 was 2.9 ± 0.1 times higher than baseline. In the control group, myocardial hypoxia was never observed, but critical levels of SO2 and ER were noted at this stage. Yet, O2 was not extremely high; it was only 3.7 ± 0.3 times the baseline value. This is noteworthy because walking at normal pace can produce a fivefold increase in O2 (14), which, again, suggests that the increase in O2 caused by shivering may be less well tolerated than a corresponding increase caused by exercise.
Some study limitations warrant consideration. First, did the anesthetic technique affect the results? We used a balanced opioid-midazolam technique. Although most anesthetic drugs seem to alter thermoregulation, midazolam has minimal effects in this respect (9). Although fentanyl tends to decrease shivering (9), it clearly did not prevent intense shivering in our model. The use of pancuronium, however, probably affected the results (18). The increase in HR with decreasing body temperature while muscle relaxation was maintained with continuous pancuronium infusion is in contrast to previous observations; cooling usually decreases HR in deeply anesthetized animals (19). Comparison with a similar study model in which we used vecuronium (20) indicates that pancuronium was responsible also for the increased SVR. When the pancuronium infusion was decreased to allow shivering, there was an initial decrease in HR in both groups, and it is likely that the declining concentration of pancuronium unmasked the negative chronotropic effect of hypothermia. This explanation is corroborated by the findings of Dupuis et al. (17), who observed an increased HR, an increased incidence of arrhythmia, and signs of myocardial ischemia, despite a decrease in O2, when using pancuronium to treat patients shivering after coronary bypass surgery.
Second, were the animals normovolemic? The increase in Hgb between stages 1 and 2 (Fig. 1) indicates that hypothermia reduced the plasma volume, as previously observed by others (21). We have previously shown that 1:1 blood substitution with the Ringer-dextran 70 solution does maintain blood volume (22), and we therefore believe that the hemodilution and control animals had similar blood volumes when shivering started (stage 3). During the following stages Hgb concentration changed in both groups. The increase in Hgb at the start of shivering (comparison of stages 3 and 4; Fig. 1) in the hemodilution animals could reflect loss of circulating volume. However, CVP and PCWP actually increased, and a more likely explanation is that red blood cells were mobilized from the spleen (23) secondary to increased sympathetic activity induced by shivering, anemia, and hypothermia. The decrease in Hgb between stages 3 and 6, which was also observed in controls, was probably attributable to reabsorption of fluid from peripheral tissues stimulated by the return to normal temperature.
We conclude that in this model, intense, prolonged shivering was tolerated in all control animals and in most (6/8) of the severely anemic animals, but resulted in signs of myocardial hypoxia in two hemodilution animals.
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Acknowledgments
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Supported, in part, by grants from the Swedish Medical Research Council and the Department of Anesthesia and Intensive Care at the University Hospital of Lund, Sweden.
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Accepted for publication May 30, 2003.
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Abstract
Introduction
