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. 2012 Jan 4;590(Pt 5):1287–1297. doi: 10.1113/jphysiol.2011.223602

Colloid volume loading does not mitigate decreases in central blood volume during simulated haemorrhage while heat stressed

C G Crandall 1,2,1, T E Wilson 3, J Marving 4, M Bundgaard-Nielsen 5, T Seifert 5, T L Klausen 4, F Andersen 4, N H Secher 5, B Hesse 4
PMCID: PMC3381831  PMID: 22219334

Abstract

Heat stress results in profound reductions in the capacity to withstand a simulated haemorrhagic challenge; however, this capacity is normalized if the individual is volume loaded prior to the challenge. The present study tested the hypothesis that volume loading during passive heat stress attenuates the reduction in regional blood volumes during a simulated haemorrhagic challenge imposed via lower-body negative pressure (LBNP). Seven subjects underwent 30 mmHg LBNP while normothermic, during passive heat stress (increased internal temperature ∼1°C), and while continuing to be heated after intravenous colloid volume loading (11 ml kg−1). Relative changes in torso and regional blood volumes were determined by gamma camera imaging with technetium-99m labelled erythrocytes. Heat stress reduced blood volume in all regions (ranging from 7 to 16%), while subsequent volume loading returned those values to normothermic levels. While normothermic, LBNP reduced blood volume in all regions (torso: 22 ± 8%; heart: 18 ± 6%; spleen: 15 ± 8%). During LBNP while heat stressed, the reductions in blood volume in each region were markedly greater when compared to LBNP while normothermic (torso: 73 ± 2%; heart: 72 ± 3%; spleen: 72 ± 5%, all P < 0.001 relative to normothermia). Volume loading during heat stress did not alter the extent of the reduction in these blood volumes to LBNP relative to heat stress alone (torso: 73 ± 1%; heart: 72 ± 2%; spleen: 74 ± 3%, all P > 0.05 relative to heat stress alone). These data suggest that blood volume loading during passive heat stress (via 11 ml kg−1 of a colloid solution) normalizes regional blood volumes in the torso, but does not mitigate the reduction in central blood volume during a simulated haemorrhagic challenge combined with heat stress.

Key points

  • The capacity for humans to withstand a haemorrhagic challenge is reduced while heat stressed.

  • Identification of changes in central blood volume during simulated haemorrhage may help identify the mechanisms by which tolerance to haemorrhage is reduced during heat stress.

  • We found that the magnitude of reduction in central blood volume to a simulated hemorrhagic challenge is approximately three fold greater when individuals are heat stressed.

  • Volume loading did not change the relative magnitude of the reduction in central blood volume to that simulated haemorrhagic challenge.

  • These data show that greater reductions in central blood volume during a simulated haemorrhagic challenge while heat stressed may be a primary mechanism for impaired capacity to withstand that challenge in this thermal condition.

Introduction

Whole-body heat stress causes significant cardiovascular responses evidenced by large increases in heart rate and cardiac output, reductions in vascular conductance to splanchnic and renal beds, and profound cutaneous vasodilatation (Rowell et al. 1969a, 1970, 1971; Johnson & Proppe, 1996; Minson et al. 1998; Wilson et al. 2009; Bundgaard-Nielsen et al. 2010). Given the relative balance between the increase in cardiac output and the net increase in systemic vascular conductance, arterial pressure is generally well maintained, or slightly reduced (<10 mmHg), in the heat stressed human (Rowell et al. 1969a; Ganio et al. 2011).

In passively heat stressed subjects, the reduction in arterial pressure is greatly exacerbated during challenges such as upright tilt and simulated haemorrhage via lower-body negative pressure (LBNP; Wolthuis et al. 1974; Cooke et al. 2004), relative to when these individuals are normothermic (Lind et al. 1968; Nunneley & Stribley, 1979; Lucas et al. 2008; Keller et al. 2009; Nelson et al. 2011a). The consequences of these events range from the relatively minor inconvenience of light-headedness upon standing after a hot bath to an inability to adequately maintain blood pressure sufficient to perfuse organs, including the brain, in a heat stressed soldier who experienced a haemorrhage injury. The mechanisms by which passive heat stress compromises the control of arterial pressure are likely to be multifactorial, with recent findings pointing to a shift in the operating point to a steeper location on a Frank–Starling curve, reduced cerebral perfusion, and/or inadequate constriction of the cutaneous vessels during the hypotensive challenge (Wilson et al. 2002, 2006, 2009; Fan et al. 2008; Brothers et al. 2009a,c; Bundgaard-Nielsen et al. 2010; Crandall et al. 2010; Lucas et al. 2010; Nelson et al. 2011b). Regardless of the mechanism, the result of combined passive heat stress and central hypovolaemia is an inadequate arterial pressure necessary to provide sufficient driving force to perfuse the cerebral vasculature to maintain oxygenation necessary for consciousness.

Intravenous infusion of colloid in passively heat stressed individuals, sufficient to return central venous pressure (CVP) to pre-heat stress pressures, returned LBNP tolerance to that observed when individuals were normothermic (Keller et al. 2009). A follow-up study showed that infusion of volume in heat stressed individuals shifted the operating point of the Frank–Starling curve to a plateau portion on that curve (Bundgaard-Nielsen et al. 2010). The resultant effect of this shift was a smaller reduction in stroke volume for a given reduction in pulmonary capillary wedge pressure, an index of left ventricular filling pressure, following the infusion relative to heat stress without the infusion.

The effects of colloid infusion in passively heat stressed subjects on regional blood volume shifts, both during heat stress alone and during heat stress with LBNP, are unknown. Consistent with what was observed with stroke volume (Bundgaard-Nielsen et al. 2010), it might be presumed that the magnitude of the reduction in regional blood volumes of the central vasculature during LBNP is attenuated in the volume loaded state. Such an event would, at least to some degree, protect central blood volume during LBNP while heat stressed and thereby provide a mechanism for preservation of LBNP tolerance.

The purpose of this project was twofold. First, to test the hypothesis that in passively heat stressed individuals colloid infusion sufficient to return CVP to normothermic levels would restore regional blood volumes of the central vasculature to normothermic levels. Second, to test the hypothesis that colloid loading in the heat stressed human attenuates the reduction in regional blood volumes of the central vasculature during a simulated haemorrhagic challenge via LBNP.

Methods

Seven male subjects participated in this study. Subject characteristics were (means ± SD): age, 28 ± 6 years; height, 178 ± 5 cm; weight, 73.0 ± 9 kg. Subjects were not taking medications and were free of any known cardiovascular, metabolic, or neurological diseases. The study was approved by the Ethical Committee of Copenhagen (H-KF-090/04). Subjects were informed of the purpose and risks of this study, before providing their written consent. All procedures were performed in accordance with the Declaration of Helsinki.

Each subject swallowed a telemetry pill for the measurements of intestinal temperature (HQ Inc, Palmetto, FL, USA) and was instrumented for the measurement of mean skin temperature from the weighted average of six thermocouples attached to the skin. Mean body temperature was calculated as 0.9 core temperature + 0.1 mean skin temperature. Subjects were placed in a two-piece tube-lined suit that covered the entire body surface with the exception of the hands, feet, head and a forearm. CVP was measured upon cannulation of a vein in the arm (typically the basilic vein), with the catheter advanced to the superior vena cava. Correct placement was verified by the pressure waveform. Arterial pressure was obtained following cannulation of the brachial or radial artery. Both catheters were connected to fluid filled pressure transducers that were zeroed to atmospheric pressure 5 cm below (i.e. dorsal to) the subject's supra-sternal notch, and were maintained at this level throughout the study. Mean values of these pressures were obtained by integrating the respective waveforms via data analysis software (Acknowledge, Biopac, Goleta, CA, USA). Heart rate was quantified via R-wave detection of the subject's ECG. Subjects were placed with their lower body within an LBNP device that was mounted onto the bed of a gamma camera (Fig. 1). The LBNP device was sealed to the subjects’ skin at the iliac crest.

Figure 1. Experimental set-up of a subject within the lower-body negative pressure device while on the gamma camera.

Figure 1

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Notice the orientation of the dual head gamma camera such that it obtains anterior and posterior images from the entire torso.

Regional blood volume was assessed by scintigraphy as previously outlined (Crandall et al. 2008). Red blood cells withdrawn from each subject, were labelled with technetium-99m (99mTc) in vitro (Ultratag Mallenckrodt, Tyco Healthcare, USA), and then re-injected into the subject. During in vitro labelling (∼45 min), the subject rested supine within the LBNP device on the gamma camera table. After ∼15 min equilibration period following reinjection of the 99mTc labelled red cells, normothermic scans were performed with the dual-headed gamma camera (Skylight, Philips Medical Systems Andover, Massachusetts, USA) over the region encompassing approximately the iliac crest to the neck; depending on the subject's height. The number of counts within a region of interest (ROI) is proportional to the blood volume within that region, after accounting for changes in haematocrit. Subjects were then exposed to 5 min of 30 mmHg LBNP, the last 4 min of which gamma images were obtained. A second scan was performed following a rise in core temperature of ∼1.0°C (typically about 90 min after injection of labelled red blood cells). Subjects were then again exposed to 30 mmHg LBNP for 5 min, with gamma images likewise obtained during the final 4 min of LBNP. While still heat stressed, although water temperature was slightly reduced to attenuate the rate of increase in internal temperature, a warmed (38°C) colloid solution (HES 130/0.4, Voluven, Fresenius Kabi Copenhagen, Denmark) was infused intravenously sufficient to return CVP towards pre-heat stress levels. The infused amount was 758 ± 110 ml over ∼10 min, which equalled a volume of 11 ± 1 ml kg−1. A third scan was performed upon completion of the volume infusion. This was followed by 5 min of 30 mmHg LBNP, of which gamma images were obtained during the final 4 min.

The position of the subject was unchanged throughout the protocol. Data were acquired in a 128 by 128 matrix and stored in a dedicated acquisition station (Pegasys, ADAC Medical Technologies, Milpitas, CA, USA). Data were subsequently analysed using a computer workstation (eNTEGRA, General Electric, Milwaukee, WI, USA). The anterior and posterior projections were combined by calculation of the geometric mean of opposite views. This calculation is necessary because it compensates for counting efficiency of the labelled red blood cells if they are located superficially or deep in the body, and if they are distributed in the anterior or posterior direction. Attenuation compensation was applied from cobalt-57 transmission scans, in accordance with the principles outlined by Sorenson (1984), because without this compensation labelled red blood cells redistributed to body parts with smaller thickness (e.g. arms) would otherwise be counted with higher efficiency relative to blood redistributed to thicker body regions (e.g. torso).

Data analysis

Thermal and haemodynamic data were recorded at 100 Hz via a 16 bit A/D converter (Biopac). Data were reduced to 1 min averages throughout the following time periods during each scan: normothermia, normothermia + LBNP, heat stress, heat stress+LBNP, volume infusion, and volume infusion + LBNP.

Radioactive counts were obtained from the following ROIs: torso, heart, lungs, a region of the liver and spleen (Fig. 2). ROIs were drawn by a skilled technologist, blinded to the thermal, LBNP, and infusion conditions. After adjusting the radioactive counts within a ROI for attenuation correction, haematocrit changes (Cai et al. 2000b; Crandall et al. 2008), and 99mTc decay (6 h half-life), the effects of LBNP on changes in regional blood volumes within each ROI for each thermal condition were assessed as:

Figure 2. Scintigraphic images obtained from one subject during normothermia, normothermia plus lower-body negative pressure (LBNP), heat stress, heat stress plus LBNP, colloid infusion, and colloid infusion plus LBNP.

Figure 2

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Changes in the count rate, corrected for decay, attenuation and haematocrit changes, of the ROIs were determined to calculate relative changes in regional blood volume in the torso, heart, lungs, liver and spleen. Data are analysed from higher resolution images relative to that displayed.

graphic file with name tjp0590-1287-m1.jpg

Statistical analysis

The interactive effects of thermal condition and LBNP on haemodynamic and thermal responses, as well as the index of blood volume (i.e. radioactive counts) within each ROI were compared via two-way repeated measures ANOVA, followed by a Holm–Sidak post hoc test if a significant main effect or interaction was identified. The effect of the aforementioned thermal conditions on the percentage reduction in regional blood volume to LBNP was statistically evaluated via one-way repeated measures ANOVA, followed by a Holm–Sidak post hoc test if a significant main effect was identified. Data are reported as means ± SD. The level of significance was set at P≤ 0.05.

Results

Pre-LBNP responses

Haemodynamic and thermal responses while subjects were normothermic, heat stressed, and heat stressed plus colloid infusion are depicted in Table 1. Prior to LBNP while heat stressed, core temperature increased ∼1°C and it continued to increase resulting in a final core temperature of 38.3°C following colloid infusion. Although there was a tendency for mean arterial pressure (MAP) to be reduced during heat stress and heat stress plus colloid infusion conditions, there were no statistical differences in MAP between conditions. Typical increases in heart rate occurred to heat stress alone, but heart rate was not further changed following colloid infusion. Heat stress decreased CVP. Subsequent colloid infusion increased CVP from the heat stress alone condition, but CVP was not fully restored to pressures when subjects were normothermic.

Table 1.

Haemodynamic and temperature responses under each condition at baseline and during 30 mmHg lower-body negative pressure (LBNP)

Normothermia Heat stress Heat stress and colloid Infusion
Baseline LBNP Baseline LBNP Baseline LBNP
MAP (mmHg) 82 ± 7 81 ± 6 76 ± 7 63 ± 7* 77 ± 3 71 ± 4*
Heart Rate (bpm) 55 ± 5 64 ± 8 92 ± 9† 125 ± 20* 93 ± 9† 98 ± 6
Skin Temp (°C) 34.4 ± 0.3 34.4 ± 0.2 37.9 ± 0.2† 37.5 ± 0.1* 37.7 ± 0.4† 37.3 ± 0.2*
Core Temp (°C) 37.0 ± 0.3 37.0 ± 0.2 38.0 ± 0.18† 38.2 ± 0.21* 38.3 ± 0.3†‡ 38.3 ± 0.28
Mean Body Temp (°C) 36.7 ± 0.3 36.7 ± 0.2 38.0 ± 0.2† 38.1 ± 0.2* 38.2 ± 0.3†‡ 38.2 ± 0.3
CVP (mmHg) 6.6 ± 2.5 0.9 ± 2.5* 2.1 ± 2.6† −0.7 ± 2.7* 5.3 ± 2.3†‡ 0.8 ± 2.6*
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MAP, Mean arterial pressure; CVP, central venous pressure; Temp, temperature.

†

Different from normothermia baseline condition (P < 0.05).

‡

Different from heat stress baseline condition (P < 0.05).

*

Different from baseline within the respective thermal condition, i.e. within normothermia, heat stress, or volume infusion; P < 0.05).

Heat stress reduced regional blood volume, relative to normothermia, in all evaluated areas with the exception of the left lung. The percentage reduction in regional blood volumes to the heat stress are shown in Table 2. Subsequent colloid infusion restored blood volume in all regions resulting in blood volumes that were not different relative to normothermic conditions.

Table 2.

Percentage change in regional blood volume relative to normothermia for both heat stress and colloid infusion conditions prior to LBNP

Change in blood volume between normothermic and heat stressed conditions Change in blood volume between normothermic and heat stress plus colloid infusion conditions
Torso −11.9 ± 5.0%* 0.7 ± 3.4%
Heart −9.3 ± 4.0%* 0.5 ± 4.1%
Left lung −6.7 ± 7.8% 3.9 ± 5.3%
Right lung −14.5 ± 9.7%* 3.8 ± 9.6%
Liver −16.1 ± 8.7%* 4.4 ± 8.3%
Spleen −13.8 ± 9.1%* −1.9 ± 7.0%
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*

The reduction in the index of blood volume within the specified region of interest was greater relative to normothermia (P < 0.05). There were no differences in the indices of regional blood volume between normothermia and colloid infusion states.

LBNP responses

While normothermic, 30 mmHg LBNP did not change MAP, heart rate, skin temperature, or core temperature; however CVP was reduced by 5.6 ± 0.8 mmHg (Table 1). While heat stressed, LBNP decreased MAP (14 ± 9 mmHg) and CVP (2.7 ± 0.9 mmHg), whereas heart rate was elevated 33 ± 22 bpm. Following volume infusion the reduction in MAP (6 ± 4 mmHg) and the elevation in heart rate (5 ± 11 bpm) to LBNP were attenuated relative to these responses during heat stress alone, while the reduction in CVP (4.5 ± 1.6 mmHg) to LBNP was greater following volume infusion relative to heat stress alone.

The reductions in regional blood volumes of the central vasculature to 30 mmHg LBNP are illustrated in Figs 2 and 3. While subjects were normothermic, LBNP decreased blood volume in all ROIs, the magnitude of which ranged between 14 and 27%. When LBNP was applied to subjects while heat stressed, the magnitude of reduction in central/regional blood volumes were profound; decreasing by more than 70%. The reduction in blood volume for all ROI to LBNP following colloid infusion was not different compared with heat stress alone, but was greater than during normothermic conditions.

Figure 3. Relative reduction (mean values ± SD) in blood volume to 30 mmHg lower-body negative pressure (LBNP) in the indicated regions while subjects were normothermic, heat stressed and after colloid infusion (volume infusion).

Figure 3

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While normothermic, LBNP decreased regional blood volume from 14 to 28%. The magnitude of the reduction in regional blood volume to LBNP during heat stress and colloid infusion states was greater relative to normothermia, while there were no differences in the magnitude of this reduction between heat stress and colloid infusion conditions. *P < 0.01 compared to normothermia.

Discussion

The first objective of the protocol was to identify whether colloid volume loading sufficient to elevate CVP towards normothermic levels in heat stressed subjects would return regional blood volumes of the central vasculature to levels not different relative to when subjects were normothermic. Consistent with that hypothesis, administration of 11 ± 1 ml kg−1 of a colloid solution elevated torso blood volume, as well as blood volume in each of the evaluated ROIs, to levels that were not different relative to when subjects were normothermic. The second objective was to identify the effect of heat stress alone, as well as heat stress followed by colloid infusion, on the reduction in regional blood volumes of the central vasculature to a simulated haemorrhagic challenge, i.e. 30 mmHg LBNP. The key findings addressing this objective are that the magnitude of the reduction in torso and regional blood volumes were profoundly greater when subjects were heat stressed, with (counter to our hypothesis) and without volume loading. Although colloid infusion returned regional blood volumes to normothermic conditions, this change was only modest when compared to the magnitude of the decrease observed during simulated haemorrhage while heat stressed.

Whole-body heat stress causes large reductions in central venous, pulmonary artery, and pulmonary capillary wedge pressures (Rowell et al. 1969a; Minson et al. 1998; Crandall et al. 1999b; Wilson et al. 2007, 2009; Bundgaard-Nielsen et al. 2010). This occurs via a displacement of blood from the central circulation to the peripheral circulation (primarily the skin) to facilitate heat dissipation, coupled with increases in cardiac output (Johnson & Proppe, 1996). Although prior studies hypothesized that whole-body heat stress reduces central blood volume (Müller, 1905; Glaser et al. 1950; Eisalo, 1956; Koroxenidis et al. 1961; Frayser et al. 1966), this was not consistently observed (Rowell et al. 1969a). Using the same radiographic techniques employed in the present study, we previously identified that passive whole-body heat stress reduces central blood volume by ∼14% (Crandall et al. 2008), a value similar to the 12 ± 5% reduction in torso blood volume by heat stress identified in the present study. It was unknown whether restoration of CVP towards pre-heat stress levels would be sufficient to also return indices of central blood volume to pre-heat stress levels. Colloid infusion (11 ± 1 ml kg−1) elevated CVP close to normothermic levels, remaining ∼1 mmHg below that measured while subjects were normothermic, and was sufficient to return torso and regional blood volumes to levels similar to normothermic conditions. These findings have important implications with respect to prior studies in which the elevation of CVP in heat stressed subjects was presumed, but not confirmed, to return central blood volume to normothermic levels (Crandall et al. 1999a,b; Keller et al. 2009; Bundgaard-Nielsen et al. 2010).

The second objective of the study was to evaluate the effects of a simulated haemorrhagic challenge on changes in regional blood volumes of the central vasculature while subjects were normothermic, heat stressed, and heat stressed following colloid infusion. LBNP is a commonly used experimental perturbation to simulate orthostatic and haemorrhagic challenges (Wolthuis et al. 1974; Lategola & Trent, 1979; Polese et al. 1992; Verghese & Prasad, 1993; Ludwig & Convertino, 1994; Cooke et al. 2004). Prior evaluations report 16–26% reductions in various indices of heart or central blood volumes during 20–50 mmHg LBNP in normothermic subjects (Rowell et al. 1972; Wolthuis et al. 1974, 1975; Cai et al. 2000b). These responses are remarkably similar to the present investigation in which 30 mmHg LBNP decrease torso blood volume by 21.5 ± 7.6% and heart blood volume by 17.9 ± 6%. With an estimated central blood volume of 1.2 litres in supine humans (Rowell et al. 1969b; Rowell, 1986a), a 21.5% reduction to LBNP would represent ∼258 ml being displaced during LBNP.

Following an elevation of internal temperature of ∼1°C, the LBNP challenge was repeated. Under these thermal conditions the magnitude of the reduction in blood volumes in all assessed regions was profound relative to when subjects were normothermic (Figs 2 and 3). It should be noted that the relative reduction in blood volumes are from a lower absolute pre-LBNP blood volume, given that heat stress decreased regional blood volumes by 7–16%. Nevertheless, if normothermic central blood volume is ∼1.2 litres in the supine human, and subsequent heat stress decreases that value by 12% (Table 2), central blood volume would be ∼1.1 litres prior to LBNP while heat stressed. A subsequent 72% reduction in central blood volume from that value would equate to an absolute central blood volume of ∼300 ml during 30 mmHg LBNP while subjects are heat stressed. It should be emphasized that these calculations are based upon the assumption that relative changes in torso and heart blood volumes, as indicated by scintigraphy, accurately reflect changes in central blood volume, an assumption that has not been confirmed.

Despite returning torso and regional blood volumes to normothermic levels via colloid infusion, the magnitude of the relative reduction in torso and regional blood volumes to 30 mmHg LBNP was similar to that observed during LBNP while heat stressed without colloid infusion (Fig. 3). Thus, regardless of the modest (∼12%) restoration of central volume and a near normal CVP following colloid infusion, subsequent LBNP caused similar reductions in indices of central blood volumes while heat stressed. It is unknown whether loading of the vasculature with volumes greater than 11 ml kg−1 would have provided differing results during LBNP relative to that depicted in Figs 2 and 3.

What is the mechanism by which LBNP caused similar reductions in regional volumes while heat stressed, despite elevated central blood volume following colloid infusion? Under normothermic conditions 30 to 50 mmHg LBNP is estimated to increase lower body/limb blood volume by 500 to 1000 ml (Wolthuis et al. 1974). Based upon the present results, the capacity for the lower body to serve as a blood reservoir is greatly enhanced while individuals are heat stressed regardless of added blood volume. Consistent with this hypothesis, we found that the elevation in lower abdominal blood volume, estimated via impedance, during an upright tilt test was ∼2-fold greater when subjects were heat stressed relative to normothermic (unpublished observation). Furthermore, heated cutaneous veins have a tremendous capacity to increase blood volume (Henry & Gauer, 1950; Henry, 1951; Rowell, 1986b; Deschamps & Magder, 1990), and thus under heat stressed conditions this bed likewise serves as a potential blood reservoir within the lower body/limbs during LBNP. Additionally, the venoarteriolar response, that is the capacity for arteriolar constriction due to increases in downstream venous pressure, is greatly reduced in the heated limb (Brothers et al. 2009b). Given that the pressure in the venous system within the LBNP device is elevated during LBNP, an attenuated venoarterioalar response would likewise result in a greater blood reservoir in the lower body/legs while in the heated state, irrespective of volume status. The obvious source of the additional blood volume residing in the lower body/legs during LBNP while heat stressed is from the torso and upper limbs.

Despite similar reductions in torso and regional blood volumes to LBNP between heat stressed and heat stressed plus colloid infused conditions, tolerance to a pre-syncopal limited LBNP challenge is returned to normothermic levels following colloid infusion (Keller et al. 2009). In that study, while heat stressed all but one subject experienced syncopal symptoms resulting in LBNP termination at or before 40 mmHg LBNP; however, while similarly heat stressed but after colloid infusion every subject completed 80 mmHg LBNP. In the present study two subjects experience syncopal symptoms during LBNP while heat stressed, while this was not observed in any subject during LBNP in either normothermic or heat stress plus volume loading conditions. In these two subjects there was sufficient time prior to experiencing these symptoms to obtain the scans and thus their data were not excluded. Given similar reductions in indices of central blood volumes to LBNP, the maintenance of arterial pressure, sufficient to adequately perfuse the cerebral vasculature, must be a primary factor in determining the capacity of an individual to withstand an LBNP or related challenge. The present findings are consistent with this concept in that while heat stressed LBNP decreased MAP by ∼13 mmHg, but only ∼6 mmHg following volume infusion (Table 1). Given that arterial pressure is the product of cardiac output and vascular resistance, it is likely that volume infusion caused this effect via elevations in cardiac output. Unfortunately, we were unable to measure cardiac output in the present protocol, but in a previous protocol using a similar experimental approach (Bundgaard-Nielsen et al. 2010) the reduction in cardiac output to 30 mmHg LBNP was not different between heat stress (3.8 ± 1.1 l min−1) and heat stress plus colloid infusion conditions (4.2 ± 1.6 l min−1; P = 0.48). However, pre-LBNP cardiac output was higher for the infusion condition (13.8 ± 2.3 l min−1) relative to the heat stress alone condition (10.9 ± 2.2 l min−1; P < 0.001). This resulted in a cardiac output at 30 mmHg LBNP to likewise be higher following the infusion (9.6 ± 2.3 l min−1) relative to heat stress alone (7.1 ± 1.7 l min−1; P < 0.001). Thus, an elevated cardiac output to LBNP is likely to be the primary mechanism by which arterial pressure and thus LBNP tolerance are preserved during the infusion trials in the present and prior studies (Keller et al. 2009; Bundgaard-Nielsen et al. 2010).

A limitation of the presented work is the use of torso and regional blood volumes (e.g. the heart and lungs) as indices of the change in central blood volume to the applied perturbations. Central blood volume is defined as the volume of blood between the tricuspid and aortic valves, although components of the central venous circulation and aorta are often included. Its measurement requires injecting a tracer in the central venous circulation, close to the tricuspid valve, and sampling that tracer as close as possible to the aortic valve. In the present study 99mTc labelled red blood cells coupled with gamma camera images of torso, heart and lung blood volumes were used as the primary indices of central blood volume, clearly volumes of blood that are outside the classical definition of central blood volume. Although it remains unknown whether the magnitude of the reductions in torso, heart and lung blood volumes accurately reflects changes in the more narrowly defined central blood volume during LBNP in normothermic and heat stressed individuals, we are unaware of potential confounding influences that may limit the interpretation of the broadly defined central blood volume obtained via scintigraphy. Furthermore, the employed technique provided similar results when compared to other methods to estimate central blood volume during LBNP, namely positron emission tomography and thoracic impedance (Cai et al. 2000a).

With the employed imaging approach, we are not able to distinguish differences in blood volumes of an organ or ROI from blood volume of skin overlying those regions. Skin blood volume increases during heat stress and thus has the potential to influence the measures within the regions of interest. However, given the minimal thickness of torso skin (0.5 to 2 mm), relative to the volume of the imaged structures (i.e. heart, lungs, etc.), it is highly unlikely that small changes in skin blood volume adversely affected the estimation of blood volume changes in organs/regions under that skin. Moreover, the small reduction (i.e. ∼15%) in cutaneous vasoconstriction during pre-syncopal limited orthostatic challenges in heat stressed subjects (Crandall et al. 2010) further negates the possibility that overlying skin may adversely affect the interpretation of changes in blood volumes below that skin during LBNP.

It was not feasible to randomize the three experimental conditions (i.e. normothermia, heat stress and heat stress plus colloid infusion) as this would require each subject to receive three doses of radioactivity associated with the tracer rather than one dose employed in the present study. That said, it is unlikely that the absence of randomization adversely affected the interpretation of the results; the possible exception being the slightly higher internal temperature of the heat stress plus colloid infusion condition relative to heat stress alone condition (Table 1). Given these slight internal temperature differences, it is possible that the magnitude of the reduction in regional blood volumes during the second heat stress LBNP trial would have been greater relative to the first heat stress LBNP trial had colloid not been administered before the second heat stress LBNP challenge. Thus, there remains the possibility that colloid infusion slightly attenuated the magnitude of the reduction in regional blood volumes relative to that trial had colloid not been administered.

The present study was conducted solely on male subjects. Subsequent studies need to be conducted to identify whether the observed findings are consistent in females and whether the phase of the menstrual cycle alters those responses. Data were obtained from subjects who were passively heat stressed. It may be that responses would be different if the subjects were heat stressed actively (i.e. via exercise). However, such a study would be very difficult to perform given the relatively rapid decrease in core temperature following exercise, coupled with the duration needed to obtain the presented data.

The present data demonstrate that volume infusion with a colloid solution in heat stressed individuals restores indices of central blood volume to normothermic levels. Furthermore, the magnitude of the reduction in regional blood volumes of the central vasculature to a simulated haemorrhagic challenge (e.g. 30 mmHg LBNP) while subjects are heat stressed is ∼3-fold greater relative to when individuals are normothermic. Finally, colloid infusion does not attenuate the magnitude of the reduction in regional blood volumes of the central vasculature to 30 mmHg LBNP while heat stressed. These findings, coupled with prior related work (Keller et al. 2009; Bundgaard-Nielsen et al. 2010), may have important clinical implications towards the treatment of a hemorrhaging individual who is also hyperthermic, such as military personnel, firefighters, and mine workers. Together, these data suggest that elevations in central blood volume are beneficial for such individuals to withstand a haemorrhagic challenge, although not by mitigating the relative reduction in central blood volume during such a challenge.

Acknowledgments

The investigators express gratitude to Mia Hjorth Albers from the Department of Clinical Physiology, Nuclear Medicine and PET at Rigshospitalet, Copenhagen, Denmark for her service and professionalism in assisting with this study. The authors would like to recognize the scientific contributions, as well as friendship, of Dr Jens Marving who died while this manuscript was being prepared. This study was funded in part by the National Heart, Lung, and Blood Institute (HL 61388 and HL84072).

Glossary

Abbreviations

CVP

central venous pressure

LBNP

lower-body negative pressure

Author contributions

C.G.C.: conception and design of the experiment; collection, analysis, and interpretation of data; and drafting the article or revising it critically for important intellectual content. T.E.W.: conception and design of the experiment; collection, analysis, and interpretation of data; and drafting the article or revising it critically for important intellectual content. J.M.: conception and design of the experiment; and collection, analysis, and interpretation of data. M.B.-N.: collection, analysis, and interpretation of data; and drafting the article or revising it critically for important intellectual content. T.S.: collection, analysis, and interpretation of data; and drafting the article or revising it critically for important intellectual content. T.L.K.: collection, analysis, and interpretation of data. F.A.: collection, analysis, and interpretation of data. N.H.S.: conception and design of the experiment; collection, analysis, and interpretation of data; and drafting the article or revising it critically for important intellectual content. B.H.: conception and design of the experiment; collection, analysis, and interpretation of data; and drafting the article or revising it critically for important intellectual content. The experiments were performed in the Department Nuclear Medicine and PET, Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Denmark. All authors approved the final version of the manuscript.

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