1 MRC Trauma Group University of Manchester, University of Manchester, Oxford Road, Manchester M13 9PT, UK. 2 South Manchester University Hospitals, Manchester, UK.
Corresponding author: University Department of Anaesthesia and Intensive Care, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. E-mail: mahesan.nirmalan@man.ac.uk Declaration of interest: Dr D. J. Edwards acted as a Medical Advisor to Maelor Pharmaceuticals, Ltd.
Accepted for publication: March 6, 2003
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Abstract |
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Methods. Twenty-nine anaesthetized pigs (mean weight 27.4 kg; (SD) 3.2) were randomly allocated to three groups: control (C, n=9), shock resuscitated with either NaCl 0.9% (S, n=10), or 4% gelatine (G, n=10). Shock was maintained for 1 h followed by fluid resuscitation with either normal saline or 4% gelatine solution. Cardiac output (CO), mean arterial pressure (MAP), mixed venous saturation (SvO2), blood lactate concentration, mean pulmonary artery pressure (MPAP), MPAP/MAP, pulmonary vascular resistance (PVR), extravascular lung water index (EVLWi), PaO2/FIO2, venous admixture (Q·S/Q·T), and dynamic lung compliance (Cdyn) were measured at baseline, beginning of shock phase, end of shock phase, and post-resuscitation.
Results. At the end of volume resuscitation CO was restored to control values in both shock groups. MAP remained significantly below control values (95% CI: C=7095, S=2852, G=4569 mm Hg) in both shock groups. MPAP/MAP was significantly greater in both shock groups at the end of the shock phase (95% CI; C=0.150.24, S=0.280.38, G=0.320.42) and at the post-resuscitation phase (95% CI: C=0.120.30, S=0.430.61, G=0.320.49) indicating the presence of relative pulmonary hypertension. This was associated with a significant increase in PVR in Group S (F=3.9; P<0.05). There were no significant changes in PaO2/FIO2, Q·S/Q·T, EVLWi, or Cdyn. In a small cohort of animals a measurable increase in EVLWi (>30%) and reduction in Cdyn (>10%) were observed.
Conclusions. Pulmonary vascular injury manifesting as relative pulmonary hypertension and increased PVR may occur within the first hour after the onset of shock. These changes may not be accompanied by overt changes in oxygenation, compliance, or EVLWi.
Br J Anaesth 2003; 91: 22432
Keywords: complications, pulmonary hypertension; complications, pulmonary vascular resistance; complications, shock; lung, functions; lung, water
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Introduction |
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The importance of these pathophysiological processes to the initial clinical presentation of patients following a period of sustained post-traumatic shock is not known. Hypo xaemia is a common finding in such patients even in the absence of direct chest trauma and consequently the routine administration of oxygen is recommended in the Advanced Trauma Life Support protocols.10 While ventilation/perfusion mismatch, aspiration of gastric contents and fluid overload during initial fluid resuscitation are considered possible causes, shock mediated endothelial changes are rarely considered important at this very early stage. Characterizing the role of shock per se on pulmonary function, however, is important in order to initiate appropriate therapies for these patients. For example, observed increases in EVLW (manifesting as hypoxaemia associated with pulmonary oedema or fine basal crepitations over the lung fields) when wrongly attributed to iatrogenic fluid overload frequently leads to fluid restriction or even the use of diuretics with potentially serious consequences in patients who are already volume depleted. The choice of resuscitation fluids continues to draw considerable interest and debate amongst critical care physicians in this context. This is particularly relevant in the light of three recent meta analyses that showed conflicting results on the choice of resuscitation fluids on clinical outcome.1113 The current clinical consensus, however, is that the choice of resuscitation fluids does not influence the immediate or long-term pulmonary outcome in patients with post-traumatic shock.14 15 In the light of these uncertainties we undertook the following study in a laboratory model of sustained post-traumatic shock to test the following hypotheses.
Primary hypotheses
A combination of standardized skeletal injury followed by a period (1 h) of acute hypovolaemic shock in the anaesthetized pig may reproduce the physiological abnormalities consistent with those described in human victims of post-traumatic shock and thereby be of relevance in the study of pulmonary changes in shock.
That in such a model an increase in EVLW and other features of pulmonary vascular dysfunction are demonstrable before fluid resuscitation is commenced and these changes continue to be an integral component of the overall pathophysiological profile even after initial volume replacement.
Secondary hypothesis
The nature of fluids (crystalloids or colloids) used in initial resuscitation does not influence early changes in EVLW content or other pulmonary functions.
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Methods |
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Using aseptic techniques, the right external jugular vein was exposed and a pulmonary artery floatation catheter (Baxter Swan-Ganz CCO/VIP, 7.5F; Edwards Life Sciences, CA, USA) was introduced. Correct positioning of the pulmonary artery catheter was confirmed by inspecting the transduced waveforms. All animals received maintenance fluids (NaCl 0.9%; 10 ml kg1 h1) via the central vein to replace insensible fluid loss (this infusion was discontinued during the shock procedure and restarted after resuscitation). The femoral artery was then exposed surgically and the dilution catheter (Pulsiocath PV 2024 4F; Pulsion Medizintechnik, Munich, Germany) was positioned in the abdominal aorta. An indwelling suprapubic Foley catheter was positioned for continuous drainage of urine. At the end of the instrumentation phase (considered time 0) all animals were given a rest period of 30 min following which baseline measurements were made. This was followed by the shock procedure in Groups S and G. A captive bolt (Cox Universal model V/10165; Temple Cox Development, Bromley, Kent, UK) was used to achieve bilateral tibial fractures. The bolt was applied directly to the bone in order to minimize soft tissue damage. Haemorrhage was then commenced at a rate of 1 ml kg1 min1 and continued until three of the four predetermined end points of shock were achieved. Shock was achieved in all animals within 30 min and the end points for shock were as follows.
1. Greater than 30% reduction in CO.
2. Greater than 30% reduction in mean arterial pressure (MAP).
3. Mixed venous oxygen saturation (SvO2) less than 40%.
4. Blood lactate concentration greater than 3 mmol litre1.
Shock was maintained for 1 h (shock phase) and further blood was removed as necessary during this phase in order to ensure at least three shock criteria were maintained throughout this period. Start of shock phase measurements and end of shock phase measurements were made at the beginning and end of the shock phase, respectively. At the end of the shock phase, volume resuscitation was achieved with either NaCl 0.9% (S group) or gelatine (G group). Fluid administration was stopped when CO was restored and maintained above 90% of baseline values throughout the resuscitation phase (60 min) followed by the post-resuscitation phase measurements. The animals were killed by anaesthetic overdose, chest opened, lungs removed, and EVLW content was determined by a gravimetric method, which corrects for intravascular volume.16
Measurement of extravascular lung water index
The dual dye dilution method (COLD Z-03; Pulsion Medizintechnik, Munich, Germany) was used to estimate extra vascular lung water index (EVLWi) at the following time points.
1. Baseline: 30 min after completion of the instrumentation phase.
2. Start of shock phase: 60 min after completion of the instrumentation phase.
3. End of shock phase: 120 min after completion of the instrumentation phase.
4. Post-resuscitation phase: 180 min after completion of the instrumentation phase.
Triplicate estimates of EVLWi using a manual injection of 10 ml of cold indocyanin green (Pulsion; 1 mg ml1) were made and the numerical average of the two closest measurements was taken as the true EVLWi for each phase. Dynamic lung compliance (Cdyn), PaO2/FIO2 ratio, venous admixture (Q·S/Q·T), mean pulmonary arterial pressure (MPAP), MAP, CO, arterial blood lactate concentration were also measured at the same time points as EVLWi in all three groups. A stopwatch was used in all experiments in order to make the respective measurements at the same time points in the three groups.
Measurement of dynamic lung compliance (Cdyn)
A tracheal tube with a purpose-built pressure monitoring port was used to intubate the trachea (Mallinkrodt, Hi-Lo Jet; size 6.5). An oesophageal balloon (Mallinkrodt, size 8.5) was positioned in the mid-oesophagus and the pressure monitoring ports of both tubes were connected to a differential pressure transducer (Pneu-01; World Precision Instruments, Inc., USA) to obtain transpulmonary pressure signals. A Pneumotachograph (Godart 17212; Gould Electronics BV, The Netherlands) was used for respiratory flow measurements. Transpulmonary pressure and respiratory flow signals were acquired and stored in a personal computer using standard equipment and software (CED 1902, CED 1401 and Spike 2; Cambridge Electronics Design, Cambridge, UK). Tidal volume was obtained by integrating the inspiratory flow signals and Cdyn was calculated17 for baseline, end of shock, and post-resuscitation phases.
Measurement of pulmonary venous admixture (Q·S/Q·T) and blood lactate concentrations
Arterial and mixed venous blood samples were obtained simultaneously during the four phases of measurement. Mixed venous blood was sampled using a low pressure aspiration technique to prevent contamination with left atrial blood18 and the samples were analysed immediately in the blood gas analyser/oximeter (ABL 330/OSM3; Radio meter, Copenhagen, Sweden) and lactate analysers (BEG 2300; YSI Ltd, UK).
CO and systemic/pulmonary vascular resistance
Using the Vigilance continuous CO monitor (Baxter Healthcare Ltd, CA, USA) continuous cardiac output (CCO) and intermittent thermodilution CO were determined. CO data used in all subsequent analyses are based on values obtained using the intermittent technique. The CCO measurements were used to identify the end points of shock and adequacy of fluid resuscitation only. Pulmonary vascular resistance (PVR) was derived from MPAP, pulmonary capillary wedge pressure (PCWP) and CO in the customary fashion: PVR=[(MPAP PCWP)/CO]*80. As right atrial pressure measurements were not made (because of technical difficulties inherent in placing an additional catheter in the right atrium) a proxy measure of systemic vascular resistance (SVR) was derived in the following way: SVR=MAP/CO*80.
Statistical analyses
All variables were analysed using analysis of variance (ANOVA) for repeated measurements (general linear model; SPSS 9.0, SPSS, Inc., Chicago, IL, USA). Change in PVR during the course of the experiment (PVRpost-resuscitationPVRbaseline) was compared between the groups using one-way ANOVA. When using the repeated measures ANOVA, significant factors were further compared using 95% CI of the estimated means at each of the four phases of the experiment. Statistical significance was defined as P<0.05 (two-tailed). As all data were normally distributed mean (SD) and corresponding ranges have been used as summary statistics.
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Results |
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Mean SV at the post-resuscitation phase was substantially less in Group S than in Groups C and G even though this difference did not reach statistical significance (95% CI: C=23.533.9, S=16.627, G=23.133.5 ml). When compared with baseline values, however, both shock groups showed a significant reduction (LVSWpost-resuscitation LVSWbaseline) in LVSW (F=19.4, P<0.001) closely following the observed trends in MAP. Mean SvO2 recovered to above 40% after resuscitation but remained significantly below control in both shock groups, reflecting haemodilution and a reduction in oxygen delivery consequent on the asanguineous fluids used.
Blood lactate concentration continued to rise after resuscitation in Groups S and G. Post-hoc analysis, however, showed that this apparent worsening of shock occurred only in those animals that met all four shock criteria (n=12) before the end of the shock phase (Fig. 1). In order to explain the underlying reasons for persistent hyper lactataemia in these animals further post-hoc comparisons between oxygen delivery (DO2), oxygen consumption (VO2) and arterial-mixed venous oxygen content difference [C(av)O2] was made between three post-hoc groups [C: control group (n=9); B: group of animals that did not meet the lactate criteria during the shock phase (n=8) and A: group that met the lactate criteria during the shock phase (n=12)]. The results are summarized in Table 3. In both shock groups the mean DO2 following volume replacement was less than the control groups with a greater and statistically significant reduction in Group A (95% CI: C=313443, B=215346, A=176298 ml min1). This reduction in DO2 was, however, not accompanied by a corresponding increase in C(av)O2 in either shock group. (95% CI for C(av)O2 at the post-resuscitation phase: C=3550, B=2741, and A=3547 ml litre1). There was no significant difference in the volume of blood loss between groups that met all four shock criteria and those that met only three of the four criteria (41% (9); range 2560 vs 36% (8); range 2450% of total blood volume).
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A comparison between the COLD system and gravimetric methods showed that the former method consistently underestimated EVLWi (Bland-Altman plot: bias=64 ml; SD=44 ml). At post-mortem examination it was observed that three animals (S=2; G=1) had increased amounts of fluid within the pleural and pericardial spaces. All three showed a greater than 30% increase in EVLWi and two died during resuscitation.
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Discussion |
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Post-traumatic shock has three important facets: hypovolaemia, pain, and tissue injury and it is recognized that haemodynamic responses to haemorrhage are altered significantly by concomitant nociception and injury.19 20 As both local and systemic factors are important in the evolution of lung injury bilateral long bone fractures and haemorrhage were included in the present model. The end points of shock in most published laboratory work have been based on removal of a predetermined percentage of blood volume,19 20 removal of blood until a predetermined arterial blood pressure was achieved21 or alterations in resting membrane potential (RMP).3 Clinical evaluation of shock, however, is based on the extent of global blood flow reduction and the consequences of tissue ischaemia. To the best of our knowledge this is the first study that took a combination of blood flow-based measurements (CO) and clinical measures of tissue ischaemia (SvO2 and blood lactate concentration) in the definition of shock in laboratory models. The threshold value for blood lactate concentration was 3 mmol litre1 as patients with blood lactate concentration greater than 3 mmol litre1 on admission to an emergency department are known to carry a worse prognosis than others.22 In the UK, victims of major trauma and shock receive fluid resuscitation at the site of injury by trained paramedical staff as an immediate priority. As a result, untreated shock lasting for more than an hour is rare and the shock phase in the present study was restricted to one hour in keeping with this clinical reality.
The choice of anaesthetic agent is always difficult, as all agents will modify the cardiovascular responses to trauma and shock to some extent. Saffan was chosen for most part of the study as it is the only agent that has been shown to preserve the cardiovascular responses to trauma.23 Halothane was used at the beginning to facilitate intubation without neuromuscular blocking agents and a predominantly Saffan based anaesthetic regimen was used as soon as vascular access was established. Some important limitations of the study, however, require emphasis. Most importantly, volume replacement was stopped when CO was restored and maintained to within 90% of baseline as it was essential to limit the volume of clear fluid administered to prevent unacceptable levels of haemodilution and premature death. Both shock groups were therefore under-resuscitated by design. A low MAP associated with inadequate volume resuscitation and a normal MPAP associated with hypoxic pulmonary vasoconstriction (as a result of low SvO2)24 may also account for the observed changes in MPAP/MAP and PVR. Adequate resuscitation after major haemorrhage requiring blood transfusion and volume replacement with clear fluids always raises the question of volume overload (absolute or relative to a constricted circulation) in relatively short experimental studies such as ours. As the primary hypothesis was that shock per se results in increased EVLW, under resuscitation would not have been important had we demonstrated a significant increase in EVLWi. As an increase in EVLWi was not demonstrated and the conclusions are based on changes to pulmonary and systemic arterial pressures, adequacy of volume resuscitation is an important confounding factor. In this context some of the incidental findings reported in a more recent study are extremely pertinent and should be considered along with our findings. In a similar study by Chiara and colleagues,21 (with a shock period of 1 h followed by fluid/blood resuscitation over 2 h) in spite of adequate resuscitation (including restoration of haemoglobin and MAP) MPAP, the ratio MPAP/MAP and PVR remained significantly higher than the corresponding baseline values. As the study was not designed to evaluate the pulmonary consequences of shock the above authors did not explore these incidental findings further or comment upon their significance. The significant reduction in SVR in the present study (at the post-resuscitation phase) suggests that sympathetically mediated vasoconstriction was overcome by the effects of reperfusion. Further, in the two animals that died relative pulmonary hypertension was associated with a large increase in EVLW (>30%), reduction in Cdyn, and increased fluid within the pleural and pericardial spaces. These additional features and the data reported by Chiara and colleagues21 support our conclusion that pulmonary vascular changes may begin within the first hour after the onset of shock. This observation, if confirmed by further clinical studies is very relevant to the management of patients with prolonged shock.
Many of the derived haemodynamic parameters (SV, LVSW, SVR, and PVR) are invariably linked to changes in CO, HR, MAP, and MPAP. Nevertheless, such derived parameters remain popular and useful in the critical care setting and, therefore, we have applied them to the present study. Right atrial pressure measurements were not made and, therefore, a surrogate measure of SVR has been used to assess the systemic vascular bed. Inclusion of right atrial pressure in the derivation of SVR is likely to amplify the observed differences in SVR even further (because of the lower MAP in the two shock groups) and this makes the reported differences relevant. The derivation of SVR during the shock phase (or PVR for that matter) is based on the assumptions that blood flow through a constricted circulation is laminar and blood is a Newtonian fluid.25 Both assumptions are invalid in the presence of profound vasoconstriction and hypovolaemia and this is a recognized limitation of calculated vascular resistance. Therefore, all comments on SVR and PVR are based on measurements made at baseline and during the post-resuscitation phase only. Thirdly, the duration of the instrumentation phase varied during the period of study as a result of the learning curve inherent in undertaking surgical instrumentation. This effect, however, was taken into account in the experimental design by adhering to a strict randomization protocol.
Early changes in lung function has been reported previously in pigs by Noble4 and in baboons by Holcroft and colleagues.3 The lack of a control group in Nobles study design renders the findings inconclusive and the clinical significance of shock defined by RMP criteria by Holcroft and colleagues is unclear. We have, therefore, used more clinically relevant criteria such as CO, MAP, blood lactate concentration, and SvO2. The study shows that in the early stages of shock commonly monitored parameters such as PaO2/FIO2, Q·S/Q·T, Cdyn, and EVLWi may remain unaltered (except in the more severe and irreversible forms of shock). Changes in relative pulmonary pressures (MPAP/MAP) may in fact be the earliest evidence of pulmonary vascular changes in such patients. The present study clearly highlights the differences between pulmonary and systemic vascular beds to ischaemic reperfusion. Translocation of gut-derived endotoxins into the systemic circulation following mesenteric ischaemia is a well-recognized cause for intense pulmonary vasoconstriction associated with systemic vasodilatation.6 26 We believe this is one of the possible explanations for the differences in the systemic and pulmonary circulations seen after volume replacement in the present study.
The reasons for a persistent elevation in blood lactate concentration in some animals even after fluid resuscitation is complex. Post-hoc analysis shows that even though fluid resuscitation resulted in improvements in DO2 post-resuscitation DO2 values were substantially below that of the control group and baseline values for each of the post-hoc groups. In spite of the low DO2 global oxygen extraction (reflected by C(av)O2) remained within normal limits. This implies that a combination of reduced oxygen delivery and defective extraction contributed to the persistent elevation in blood lactate concentration. In keeping with current clinical consensus14 15 no major differences were seen between the two groups resuscitated with either gelatine or saline. Both shock groups showed a significant reduction in mean SVR associated with an increase in mean PVR following volume resuscitation. The lack of a statistically significant rise in PVR for Group G we believe, is attributable to the relatively small numbers of animals in each group. The calculation of sample size, however, was based on the number of animals required within each group to demonstrate a more than 20% rise in EVLWi during the study period. Thus, even though the study was not specifically powered to demonstrate differences between the two fluid groups, differences if any are likely to be small and unimportant. The percentage blood volume removed from each group was similar (Group S=39.4% (SD=6.7%); Group G=39.1% (SD=11.6%)) although the amount of blood removed from individual animals ranged from 2460% of total blood volume highlighting the limitations of many traditionally used shock models based on fixed percentage volume loss.19 20 The present finding is in keeping with the clinical observation that the haemodynamic and metabolic consequences of haemorrhage and shock vary markedly in healthy subjects.
In conclusion, the present study suggests that pulmonary and systemic vascular dysfunction may be demonstrable within the first hour after the onset of shock. As such the stage for subsequent development of acute lung injury and or multiple organ failure may be set very early in the clinical course of shock and should be an important consideration in the initial resuscitation of patients presenting with shock. As a result of ethical and financial constraints it was not possible to include larger numbers of animals in the present study and therefore further laboratory studies where DO2 and SvO2 values are restored and maintained over a longer period are necessary to confirm the above findings and to elucidate the pathophysiology of early pulmonary changes in shock.
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Acknowledgements |
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References |
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