Clin. Radiol. (1977) 28, 315-322
THE PULMONARY MANIFESTATIONS OF SEPTIC SHOCK F. G. ADAMS and I. McA. LEDINGHAM The Western Infirmary, Glasgow
Septic shock carries a high mortality. It is manifest haematologicaUy by thromobocytopaenia and other coagulation disturbances. The radiological manifestations are various degrees of pulmonary oedema, usually affecting the lower zones, without evidence of pulmonary hypertension. Radiological signs are always preceded or accompanied by thrombocytopaenia.
INTRODUCTION There are many causes of pulmonary oedema, but one that may not be widely known is that which occurs in association with septic shock. The respiratory manifestations of this condition are associated with haematological and coagulation disturbances indicating disseminated intravascular coagulation (D.I.C.). These disturbances include thrombocytopaemia, prolongation of the partial thromboplastin time and elevation of fibrin degradation products. We have been unable to fred in the radiological literature any article dealing specifically with the 'shock lung' syndrome caused by septicaemia. Excellent articles by Joffe (1970), Bredenberg et al. (1969), and Putman et al. (1973) describe 'shock lung' but in their patients the aetiology of the shock state was usually haemorrhage. The aim of this study is to document the radiological features of this syndrome and to demonstrate a relationship between radiological signs and haematological or other data. MATERIALS AND METHODS During the period July 1972 to March 1973 21 consecutive patients suffering from septic shock were investigated in a prospective study. The clinical criteria for inclusion in the study were hypotension, vasoconstriction, mental confusion and oliguria in a patient with major sepsis. Serial blood and tissue cultures were obtained; direct arterial pressure, central venous pressure, electrocardiography, urinary output and core/peripheral temperature gradient were routinely monitored. The haemoglobin, white cell count, platelet count, prothrombin time, fibrin degradation products and Paper read at the Royal Society of Medicine on 17 January 1975.
partial thromboplastin times were analysed daily or more often if necessary. Frequent measurements of arterial oxygen tension (pO2) carbon dioxide tension (pCO2) and pH were made. The alveolar arterial oxygen tension [(A-a)O2 gradient] was calculated from the standard formula. An AP supine radiograph was taken daffy or more often as required. The AP projection was necessary as all the patients were in the intensive Care Unit. Details of the radiographic exposures were recorded to obtain a comparable series of radiographs. Cliitical and radiological signs were scored so that they could be correlated with pulmonary function studies and haematological data. Clinical signs were scored as follows: hypotension was allowed one point for each 10 mmHg below the patient's normal systolic blood pressure. Vasoconstriction was present when the difference between skin and core temperature was in excess of 4°C. One point was scored for each degree Celsius above this value. Thus a patient whose systolic blood pressure fell by 60 mmHg and skin/core gradient was 12°C would have scored 14 points. The radiological score was an indication of the degree of pulmonary oedema. Interstitial oedema was subjectively and ordinally graded as minimal, moderate, extensive or complete. Each grade scored 10 points. The criteria of interstitial oedema were perivascular and peribronchial cuffing and the assigned grade depended on whether the process was confined to the hilar regions or, in more severe cases, extended progressively towards the periphery of the lung. Alveolar pulmonary oedema was graded in relation to the area of parenchymal shadowing. The perihilar and basal zones each scored 20 points while the mid and apical zones each scored 10 points. The scores for the lower zones were weighted because of their greater contribution to lung function and volume.
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Thus, the maximum radiological score was 100 points. Complete interstitial oedema was presumed to coexist with extensive parenchymal shadowing. As the radiological score is subjective and the scale of measurement ordinal, the requirements of sophisticated statistical tests could not be met. Thus the Spearman Rank order correlation test was employed.
before treatment. Septal lines were not observed in any of our patients and cardiomegaly was not seen in the absence of pre-existing heart disease. Of the 21 patients, three showed evidence only of interstitial pulmonary oedema. In the remaining 18 patients there was a characteristic distribution of alveolar oedema in' that pulmonary shadowing decreased from base to apex. The basal regions were always involved. Pulmonary oedema may present as an ill-defined haze of relatively low density and can mimic free pleural fluid lying along the posterior chest wall. However, in the few cases in which a lateral radiograph was obtained there was no evidence of such fluid. A nodular pattern which is commonly seen when the 'shock lung' state is due to fat embolism was not observed in our cases. There was no significant correlation between central venous pressures and the degree of pulmonary oedema. Thrombocytopaenia. - The mean values and standard errors of the platelet counts are shown in Fig. 1. Although thrombocytopaenia developed after the clinical signs of shock, it always preceded the radiological changes and also persisted for a longer time. Thrombocytopaenia was usually profound and in 57% of our cases the platelet count fell to below 50 000/cm 3.
RESULTS The ages of the patients ranged from 26 to 73 years with a mean of 53.9 (s.d. -+ 18.8). The ratio of males to females was approximately equal and there was no significant difference between the mean ages of males and females (P > 0.05). Clinical Signs. - The mean clinical scores and their standard errors are shown in Fig. 1. The patients were most shocked on the day of admission to the Intensive Care Unit. In 13 of the 21 patients this state was reversed within 24 h. Radiologieal Signs. - The mean radiological scores and standard errors are also plotted in Fig. 1. Radiological signs appeared later than clinical evidence. Chest radiographs on admission were usually normal or nearly so. However, by the following day 20 of the 21 patients exhibited significant pulmonary oedema. Despite clinical improvement the radiological signs continued to deteriorate, generally until the third day after admission. Although the radiological signs are those of pulmonary oedema it is emphasised that no patient had evidence of pulmonary venous hypertension
Correlation Between
Radiological and other
Findings. - Phenomena such as pulmonary shadowing and thrombocytopaenia may become evident at
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THE PULMONARY MANIFESTATIONS OF SEPTIC SHOCK
317
PATHOPHYSIOLOGY OF SEPTIC SHOCK
Endotoxins ]
1 1
Activation of proteolytic enzymes
Renin f angiotensi 7
platelet aggregation + release
Vasoconstriction ~ Peripheral pooling
Cardiac output
~ anoxia
. D. I. C.
L
/
oedema
Venous return~ J 4 Fig. 2 - Pathophysiology of septic shock.
different stages of the disease. Correlations were therefore performed when these particular features were most obvious; i.e. radiolegical signs of the third day were correlated with platelet counts of the fourth. Radiological signs correlated well with thrombocytopaenia (r s = -0.66; P < 0.025) and the (A-a)O~ gradient (r s = 0.69, P < 0.05). There were no significant correlations between radiological signs and other haematological values or clinical signs. DISCUSSION Patho-physiology of Septic Shock. - This is illustrated diagrammatically in Fig. 2. It is stressed that this is a simplified example and in part based on the results of animal experiments. It appears that endotoxin does not act directly on the vessel wall but its action is mediated through a heat-labile serum factor which forms proteolytic substances (Spink, 1962). The latter act on elements or cells in the blood causing the release of vaso-active substances including histamine (Spink, 1962), serotonin (Davis et al. 1961), acetylcholine and bradykinin (Thai et al., 1965) and catecholamines (Spink, 1962). These vaso-active substances, in particular the catecholamines, stimulate the alpha-receptors of arterioles and venules and lead to diffuse vasospasm (lAllehei et al., 1964), which slows the circulation and allows an accumulation of lactic acid and a fall in plasma pH. If this situation continues, the arterioles relax because their alpha-receptors are refractory.
Concurrently, venules remain constricted as they are more resistant to acidosis, since they normally operate at a lower pH. The result is pooling of blood in peripheral capillaries and reduction of cardiac output due to diminished venous return. In the capillaries this stagnant acidotic blood is hypercoagulable. However, some other factor is needed to initiate the clotting mechanism. A factor known to initiate clotting - endotoxin - is already present in the blood. Thus, disseminated intravascular coagulation occurs with the formation of microthrombi of aggregated platelets and degraded products of coagulation. Aggregation of platelets is associated with the platelet release p h e n o m e n o n which liberates more vaso-active substances and thromboplastins and this may initiate a vicious cycle of events. In the microcirculation, vasospasm, stagnant anoxia and microemboli cause interstitial oedema. The precise mechanism is uncertain but damage to vascular endothelium and cell membranes is probably more important than local haemodynamic changes due to microemboli. Microemboli and interstitial oedema also aggravate diminished venous return and cardiac output. Finally, endotoxin may directly damage myocardial muscle cells and thus reduce myocardial contractile force (Hinshaw et al., 1972). Clearly the treatment of this condition will include eradication of infection and, hence, of endotoxins. However, this may be a slow process and the primary goal must be reversal of the patient's state of shock. The combination of stagnant acidotic
318
CLINICAL RADIOLOGY
blood and endotoxin can produce disseminated intravascular coagulation. If tissue perfusion can be increased anoxia will be relieved, lactic acid accumulation prevented and the more rapidly moving circulation will be less susceptible to D.I.C. Tissue perfusion is improved by administration of large volumes of intravenous fluids to the point of elevating central venous or pulmonary artery pressure. By the same manoeuvre, venous return will be increased. The foregoing account outlines the pathophysiology and the basic principles of treatment Of septic shock a n d emphasises the difference between the management of pulmonary oedema due to septic shock and that due to heart failure or fluid overload. Septic shock and D.I.C. are often part of a complex series of events. The patient may have undergone emergency surgery for an abdominal catastrophe, or have received intravenous fluids, or suffer from cardiac or respiratory disease. Surgical complications are an additional hazard. Thus the appearance of pulmonary oedema may not be unexpected. It is important for the radiologist to be aware of clinical situations which give rise to septic shock and D.I.C. and the possibility should be borne in mind when, for example, examination is requested for subphrenic infection. In a previous study, Ledingham e t al. (1975) reduced the mortality of patients with septic shock from 73 to 38%. However, this is still a high mortality for a non-malignant condition. Septic shock is not rare and indeed most clinicians or radiologists working in a busy general hospital may encounter a number of cases each year. In our own hospital approximately 40 such patients are admitted annually to the Intensive Therapy Unit. As only severely ill patients are admitted to this unit it is not possible to calculate the true incidence of the condition. RESULTS Since a strong clinical impression prevailed that there was a close relationship between the various components of the syndrome of D.I.C. it was decided that only a small number of patients required study to produce a significant correlation. The low correlation between the radiological and clinical score is disappointing. It may be explained by the fact that the indices of shock used are inadequate. More sensitive indices exist, such as blood/urine urea ratio, but these measurements were recorded too infrequently to be of value in our study. Other possible reasons are that clinical scores may have already been modified by treatment, or that clinical
signs are more labile and variable than radiological evidence. None of these patients had pulmonary changes without prior or concomitant haematological disturbances. Thus if the radiologist suspects septicaemia as a cause of pulmonary oedema, then thrombocytopaenia should be present. Whereas only 38% of the patients had abnormal chest radiographs on the day of admission, 86% had platelet counts below 150 000/cm 3. Radiological changes usually revert to normal before the haematological disturbance recovers. Thus, it is our practice to maintain these patients on active treatment until the haematological disorders respond, irrespective of radiographic or clinical improvement. One of the aims of this study was to discover the relative value of clinical signs, haematological data and radiology in the management of this condition. Apparently haematological disturbances, especially the platelet counts, are the most useful guides. Although close correlation between radiological changes and thrombocytopaenia is gratifying, this does not imply that pulmonary oedema is caused by thrombocytopaenia. Indeed this is almost certainly a false correlation due to the underlying mechanism of septic shock which causes both pulmonary changes and D.I.C. However, it does prove that it is possible to correlate the appearances of a chest radiograph with more simple biochemical or clinical measurements. There is ample experimental evidence to suggest that microemboli are not the major cause of pulmonary changes (Ollson, 1972). It is not known whether disseminated intravascular coagulation is a coexistent phenomenon of endotoxaemia or whether it plays an important role in initiating pulmonary changes, possibly by causing increased permeability of endothelium and basement membranes. Involvement of the lower zones in all our patients who had parenchymal changes is puzzling. The absence of upper lobe diversion and the presence of normal CVP and ECG findings suggest that it is not due to left heart failure. Surfactant, which is composed basically of three phospholipids, is produced by the granular pneumocytes. The phospholipids are not manufactured by these alveolar cells and so have to be transported via the blood stream. As blood flows preferentially to the lower zones, then these regions will be affected by microemboli in D.I.C. This may lead to impairment of surfactant mechanisms and microatelectasis. Indeed, histological examination shows widespread microatelectasis and fibrinous intra-alveolar membranes in addition to pulmonary oedema. These pathological changes, which resemble the respiratory distress syndrome rather than simple
THE PULMONARY MANIFESTATIONS OF SEPTIC SHOCK
319
pulmonary congestion, help to explain why the oedema of the 'shock lung' syndrome will not respond to conventional therapy. RADIOLOGICAL DIFFERENTIAL DIAGNOSIS As septic 'shock lung' frequently occurs in the post-operative period, the differential diagnosis will include cardiac failure, fluid overload, aspiration, infarction, pulmonary oxygen toxicity and infection, including that due to Pseudomonas aeruginosa. A logical approach to the diagnosis requires consideration of the following points.
Fig. 3
(A.L.)Fulminating septic shock lung.
Fig. 4 (a, b) - (JAM.) Pulmonary venous hypertension superimposed upon seplic shock lung.
1. Pulmonary shadowing which does not predominantly involve the basal regions of the lung is unlikely to be due to septic shock. 2. Conditions with predominant basal involvement which do not exhibit interstitial oedema are unlikely to be due to septic shock. 3. Although septic shock causes pulmonary shadowing and interstitial pulmonary oedema it does not, unlike cardiac failure or fluid overload, cause redistribution of blood to the upper zones.
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A l t h o u g h t h e diagnosis o f septic s h o c k is usually e s t a b l i s h e d b y h a e m a t o l o g i c a l findings the radiological a p p e a r a n c e s are still i m p o r t a n t b e c a u s e o f t h e c o m p l e x i t y o f t h e changes w h i c h occur. F o r e x a m p l e , o n c e t h e clinical diagnosis is e s t a b l i s h e d , s u b s e q u e n t r e d i s t r i b u t i o n o f b l o o d to t h e u p p e r z o n e s w o u l d suggest left v e n t r i c u l a r failure i n a d d i t i o n t o t h e 'shock lung' syndrome. N o n e o f o u r p a t i e n t s was o n s u f f i c i e n t l y h i g h concentrations of oxygen long enough to produce p u l m o n a r y o x y g e n t o x i c i t y , w h o s e radiological a p p e a r a n c e s are u n l i k e t h e ' s h o c k lung' s y n d r o m e . Similarly, n o n e o f o u r p a t i e n t s s u f f e r e d f r o m P s e u d o r n o n a s a e r u g i n o s a i n f e c t i o n , w h i c h can cause n o t o n l y p u l m o n a r y i n f e c t i o n b u t also e n d o t o x i c ' s h o c k lung'. ILLUSTRATIVE CASES Case 1. - Mrs A.L., a previously healthy 26 year old woman was admitted with a septic abortion. She was being given a slow transfusion to replace blood loss when she
collapsed. Given only this information and the chest radiograph (Fig. 3), the radiologist might conclude that pulmonary oedema was due to over-transfusion. However, knowing that the patient was collapsed, with a positive blood culture for coliform organisms, a central venous pressure of only 19 cm H 2 0 (on IPPV) and a platelet count of 30 000/cm 3, he should consider the diagnosis of endotoxic shock lung syndrome. Case 2. - J.M. was recovering from an anterior resection of the colon when his condition deteriorated. Blood pressure was 60/40 and his CVP was 10 cm H20. His platelet count was only 95 000/cm 3. The first chest radiograph (Fig. 4a) is almost within normal limits. However, careful inspection of the hila reveals less than normally distinct vessels and bronchi. This indicates minimal perihilar interstitial oedema but there is no redistribution of blood to the upper zones. He was treated with conventional therapy and transfusion and was making a good recovery when he became acutely dyspnoeic and again collapsed. On this occasion his central venous pressure had risen to 20 cm H20. A repeat platelet count was almost within normal limits. The chest radiograph (Fig. 4b) showed pulmonary oedema with redistribution of blood to the upper zones. These appearances are due to fluid overload superimposed on the 'shock lung' syndrome.
Fig. 5 (a, b) - (F.O.) Response of septic shock lung to intravenous fluids.
THE P U L M O N A R Y M A N I F E S T A T I O N S OF SEPTIC SHOCK Case 3. - F.O., aged 54, was admitted to the medical ward with septic cholangitis and endotoxic shock. He exhibited the usual features of shock and had a positive blood culture of coliform organisms and evidence of thrombocytopaenia. The chest radiograph (Fig, 5a) shows moderate interstitial pulmonary oedema with perihilar cuffing and
321
some basal pulmonary shadowing. The second film (Fig. 5b) was taken only 36 h later but in the intervening period the patient was transfused with some 28 pints of fluid. Interstitial pulmonary oedema has cleared which emphasises that the management of 'shock lung' syndrome is the reverse of that of heart failure or fluid overload.
Fig. 6 (a, b) - (S.K.) Development of septic shock lung and thromobocytopaenia despite 'apparent' clinical improvement.
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CLINICAL R A D I O L O G Y
Case 4, - Mrs S.K., aged 68, was recovering from an abdomino-perineal resection of the rectum when she collapsed. She was only mildly hypotensive but the platelet count was reduced to 100 000/cm 3 and the central venous pressure was 17 cm H20. A chest radiograph (Fig, 6a) revealed clear lung fields. She was treated with conventional therapy including transfusion and despite clinical improvement and a normal blood pressure, pulmonary oedema developed over the next few days. The subsequent chest radiograph (Fig. 6b) was taken when the platelet count had fallen to 30 000]cm 3. There is extensive pulmonary oedema but the central venous pressure is only 14 cm H20. This illustrates that the patient's shocked state can be quickly controlled although thrombocytopaenia and pulmonary oedema may persist for several more days. Acknowledgements. - We gratefully acknowledge the skills of the medical and nursing staff of the Intensive Therapy Unit at the Western Infirmary, Glasgow; of Mr G. Donald and the photographic staff of the University of Glasgow and of the radiographers and clerical staff of tile Department of Radiodiagnosis, the Western Infirmary, Glasgow.
REFERENCES Davis, R. B., Meeker, W. R., Jr & Bailey, W. L. (1961). Serotonin release by bacterial endotoxin. Proceedings o f the Society of Experimental Biology and Medicine, 108, 774-776. Bredenberg, C. D., James, P. M., Collins, J., Anderson, R. W.,
Martin, A. M., Jr & Hardaway, R. M. (1969). Respiratory failure in shock. Annals o f Surgery, 169, 392-403. Hinshaw, L. B., Greenfield, L. J., Owen, S. E., Black, M. R. & Guenter, C. A. (1972). Precipitation of cardiac failure in endotoxin shock. Surgery, Gynaecology and Obstetrics, 135, 39-48. Joffe, N. (1970). Roentgenologic findings in post-shock and post-operative pulmonary insufficiency. Radiology, 94, 369-375. Ledingham, I. McA., McCardle, C. S., Fisher, W. D., Maddern, M., Lees, N. W., MacDonald, J. A. E., Waddell, G. D., Milligan, G. R., Mellon, A. E. & Scott, P. D. 1L (1975). Septic shock: a three year prospective trial. Scientific Abstracts: 1st World Congress on Intensive Care, ed. I. McA. Ledingham, Publisher Bell & Bain Limited, Glasgow. Lillehei, R. C., Longerbeam, J. K., Bloch, J. H. & Manax, W. G. (1964). Nature of irreversible shock. Experimental and clinical observations. Annals o f Surgery, 160, 682-710. Ollson, P. (1972). Effects of disseminated intravascular coagulation on pulmonary circulation and respiration. International Anaesthesiology Clinics, ed. Norlander, O., pp. 173-179. Elsevier Publishing Company Limited, Amsterdam and New York. Putman, C. E., Minagi, H. & Blaisdell, F. W. (1973). The roentgen appearance of disseminated intravascular coagulation (D.I.C.), Radiology, 109, 13-18. Spink, W. W. (1962). Endotoxin shock. Annals o f Internal Medicine, 57, 538-552. Thai, A. P. & Wilson, R. F. (1965). Shock. In Current Problems in Surgery. Year Book Medical Publishers Incorporated, Chicago.
THE PULMONARY MANIFESTATIONS OF SEPTIC SHOCK F. G. ADAMS and I. McA. LEDINGHAM The Western Infirmary, Glasgow
Septic shock carries a high mortality. It is manifest haematologicaUy by thromobocytopaenia and other coagulation disturbances. The radiological manifestations are various degrees of pulmonary oedema, usually affecting the lower zones, without evidence of pulmonary hypertension. Radiological signs are always preceded or accompanied by thrombocytopaenia.
INTRODUCTION There are many causes of pulmonary oedema, but one that may not be widely known is that which occurs in association with septic shock. The respiratory manifestations of this condition are associated with haematological and coagulation disturbances indicating disseminated intravascular coagulation (D.I.C.). These disturbances include thrombocytopaemia, prolongation of the partial thromboplastin time and elevation of fibrin degradation products. We have been unable to fred in the radiological literature any article dealing specifically with the 'shock lung' syndrome caused by septicaemia. Excellent articles by Joffe (1970), Bredenberg et al. (1969), and Putman et al. (1973) describe 'shock lung' but in their patients the aetiology of the shock state was usually haemorrhage. The aim of this study is to document the radiological features of this syndrome and to demonstrate a relationship between radiological signs and haematological or other data. MATERIALS AND METHODS During the period July 1972 to March 1973 21 consecutive patients suffering from septic shock were investigated in a prospective study. The clinical criteria for inclusion in the study were hypotension, vasoconstriction, mental confusion and oliguria in a patient with major sepsis. Serial blood and tissue cultures were obtained; direct arterial pressure, central venous pressure, electrocardiography, urinary output and core/peripheral temperature gradient were routinely monitored. The haemoglobin, white cell count, platelet count, prothrombin time, fibrin degradation products and Paper read at the Royal Society of Medicine on 17 January 1975.
partial thromboplastin times were analysed daily or more often if necessary. Frequent measurements of arterial oxygen tension (pO2) carbon dioxide tension (pCO2) and pH were made. The alveolar arterial oxygen tension [(A-a)O2 gradient] was calculated from the standard formula. An AP supine radiograph was taken daffy or more often as required. The AP projection was necessary as all the patients were in the intensive Care Unit. Details of the radiographic exposures were recorded to obtain a comparable series of radiographs. Cliitical and radiological signs were scored so that they could be correlated with pulmonary function studies and haematological data. Clinical signs were scored as follows: hypotension was allowed one point for each 10 mmHg below the patient's normal systolic blood pressure. Vasoconstriction was present when the difference between skin and core temperature was in excess of 4°C. One point was scored for each degree Celsius above this value. Thus a patient whose systolic blood pressure fell by 60 mmHg and skin/core gradient was 12°C would have scored 14 points. The radiological score was an indication of the degree of pulmonary oedema. Interstitial oedema was subjectively and ordinally graded as minimal, moderate, extensive or complete. Each grade scored 10 points. The criteria of interstitial oedema were perivascular and peribronchial cuffing and the assigned grade depended on whether the process was confined to the hilar regions or, in more severe cases, extended progressively towards the periphery of the lung. Alveolar pulmonary oedema was graded in relation to the area of parenchymal shadowing. The perihilar and basal zones each scored 20 points while the mid and apical zones each scored 10 points. The scores for the lower zones were weighted because of their greater contribution to lung function and volume.
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RADIOLOGY
Thus, the maximum radiological score was 100 points. Complete interstitial oedema was presumed to coexist with extensive parenchymal shadowing. As the radiological score is subjective and the scale of measurement ordinal, the requirements of sophisticated statistical tests could not be met. Thus the Spearman Rank order correlation test was employed.
before treatment. Septal lines were not observed in any of our patients and cardiomegaly was not seen in the absence of pre-existing heart disease. Of the 21 patients, three showed evidence only of interstitial pulmonary oedema. In the remaining 18 patients there was a characteristic distribution of alveolar oedema in' that pulmonary shadowing decreased from base to apex. The basal regions were always involved. Pulmonary oedema may present as an ill-defined haze of relatively low density and can mimic free pleural fluid lying along the posterior chest wall. However, in the few cases in which a lateral radiograph was obtained there was no evidence of such fluid. A nodular pattern which is commonly seen when the 'shock lung' state is due to fat embolism was not observed in our cases. There was no significant correlation between central venous pressures and the degree of pulmonary oedema. Thrombocytopaenia. - The mean values and standard errors of the platelet counts are shown in Fig. 1. Although thrombocytopaenia developed after the clinical signs of shock, it always preceded the radiological changes and also persisted for a longer time. Thrombocytopaenia was usually profound and in 57% of our cases the platelet count fell to below 50 000/cm 3.
RESULTS The ages of the patients ranged from 26 to 73 years with a mean of 53.9 (s.d. -+ 18.8). The ratio of males to females was approximately equal and there was no significant difference between the mean ages of males and females (P > 0.05). Clinical Signs. - The mean clinical scores and their standard errors are shown in Fig. 1. The patients were most shocked on the day of admission to the Intensive Care Unit. In 13 of the 21 patients this state was reversed within 24 h. Radiologieal Signs. - The mean radiological scores and standard errors are also plotted in Fig. 1. Radiological signs appeared later than clinical evidence. Chest radiographs on admission were usually normal or nearly so. However, by the following day 20 of the 21 patients exhibited significant pulmonary oedema. Despite clinical improvement the radiological signs continued to deteriorate, generally until the third day after admission. Although the radiological signs are those of pulmonary oedema it is emphasised that no patient had evidence of pulmonary venous hypertension
Correlation Between
Radiological and other
Findings. - Phenomena such as pulmonary shadowing and thrombocytopaenia may become evident at
RADtOLOGICAL
CLINICAL SCORES
SCORES
12-
•
60-
PLATELET COUNTS 220--~-
140-
4-
20
60
0
1
i
i
r
i
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of
ADMISSION
0
O
I
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Fig. 1 - R e l a t i o n s h i p b e t w e e n c l i n i c a l scores, r a d i o l o g i c a l scores and platelet counts.
i
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i
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THE PULMONARY MANIFESTATIONS OF SEPTIC SHOCK
317
PATHOPHYSIOLOGY OF SEPTIC SHOCK
Endotoxins ]
1 1
Activation of proteolytic enzymes
Renin f angiotensi 7
platelet aggregation + release
Vasoconstriction ~ Peripheral pooling
Cardiac output
~ anoxia
. D. I. C.
L
/
oedema
Venous return~ J 4 Fig. 2 - Pathophysiology of septic shock.
different stages of the disease. Correlations were therefore performed when these particular features were most obvious; i.e. radiolegical signs of the third day were correlated with platelet counts of the fourth. Radiological signs correlated well with thrombocytopaenia (r s = -0.66; P < 0.025) and the (A-a)O~ gradient (r s = 0.69, P < 0.05). There were no significant correlations between radiological signs and other haematological values or clinical signs. DISCUSSION Patho-physiology of Septic Shock. - This is illustrated diagrammatically in Fig. 2. It is stressed that this is a simplified example and in part based on the results of animal experiments. It appears that endotoxin does not act directly on the vessel wall but its action is mediated through a heat-labile serum factor which forms proteolytic substances (Spink, 1962). The latter act on elements or cells in the blood causing the release of vaso-active substances including histamine (Spink, 1962), serotonin (Davis et al. 1961), acetylcholine and bradykinin (Thai et al., 1965) and catecholamines (Spink, 1962). These vaso-active substances, in particular the catecholamines, stimulate the alpha-receptors of arterioles and venules and lead to diffuse vasospasm (lAllehei et al., 1964), which slows the circulation and allows an accumulation of lactic acid and a fall in plasma pH. If this situation continues, the arterioles relax because their alpha-receptors are refractory.
Concurrently, venules remain constricted as they are more resistant to acidosis, since they normally operate at a lower pH. The result is pooling of blood in peripheral capillaries and reduction of cardiac output due to diminished venous return. In the capillaries this stagnant acidotic blood is hypercoagulable. However, some other factor is needed to initiate the clotting mechanism. A factor known to initiate clotting - endotoxin - is already present in the blood. Thus, disseminated intravascular coagulation occurs with the formation of microthrombi of aggregated platelets and degraded products of coagulation. Aggregation of platelets is associated with the platelet release p h e n o m e n o n which liberates more vaso-active substances and thromboplastins and this may initiate a vicious cycle of events. In the microcirculation, vasospasm, stagnant anoxia and microemboli cause interstitial oedema. The precise mechanism is uncertain but damage to vascular endothelium and cell membranes is probably more important than local haemodynamic changes due to microemboli. Microemboli and interstitial oedema also aggravate diminished venous return and cardiac output. Finally, endotoxin may directly damage myocardial muscle cells and thus reduce myocardial contractile force (Hinshaw et al., 1972). Clearly the treatment of this condition will include eradication of infection and, hence, of endotoxins. However, this may be a slow process and the primary goal must be reversal of the patient's state of shock. The combination of stagnant acidotic
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blood and endotoxin can produce disseminated intravascular coagulation. If tissue perfusion can be increased anoxia will be relieved, lactic acid accumulation prevented and the more rapidly moving circulation will be less susceptible to D.I.C. Tissue perfusion is improved by administration of large volumes of intravenous fluids to the point of elevating central venous or pulmonary artery pressure. By the same manoeuvre, venous return will be increased. The foregoing account outlines the pathophysiology and the basic principles of treatment Of septic shock a n d emphasises the difference between the management of pulmonary oedema due to septic shock and that due to heart failure or fluid overload. Septic shock and D.I.C. are often part of a complex series of events. The patient may have undergone emergency surgery for an abdominal catastrophe, or have received intravenous fluids, or suffer from cardiac or respiratory disease. Surgical complications are an additional hazard. Thus the appearance of pulmonary oedema may not be unexpected. It is important for the radiologist to be aware of clinical situations which give rise to septic shock and D.I.C. and the possibility should be borne in mind when, for example, examination is requested for subphrenic infection. In a previous study, Ledingham e t al. (1975) reduced the mortality of patients with septic shock from 73 to 38%. However, this is still a high mortality for a non-malignant condition. Septic shock is not rare and indeed most clinicians or radiologists working in a busy general hospital may encounter a number of cases each year. In our own hospital approximately 40 such patients are admitted annually to the Intensive Therapy Unit. As only severely ill patients are admitted to this unit it is not possible to calculate the true incidence of the condition. RESULTS Since a strong clinical impression prevailed that there was a close relationship between the various components of the syndrome of D.I.C. it was decided that only a small number of patients required study to produce a significant correlation. The low correlation between the radiological and clinical score is disappointing. It may be explained by the fact that the indices of shock used are inadequate. More sensitive indices exist, such as blood/urine urea ratio, but these measurements were recorded too infrequently to be of value in our study. Other possible reasons are that clinical scores may have already been modified by treatment, or that clinical
signs are more labile and variable than radiological evidence. None of these patients had pulmonary changes without prior or concomitant haematological disturbances. Thus if the radiologist suspects septicaemia as a cause of pulmonary oedema, then thrombocytopaenia should be present. Whereas only 38% of the patients had abnormal chest radiographs on the day of admission, 86% had platelet counts below 150 000/cm 3. Radiological changes usually revert to normal before the haematological disturbance recovers. Thus, it is our practice to maintain these patients on active treatment until the haematological disorders respond, irrespective of radiographic or clinical improvement. One of the aims of this study was to discover the relative value of clinical signs, haematological data and radiology in the management of this condition. Apparently haematological disturbances, especially the platelet counts, are the most useful guides. Although close correlation between radiological changes and thrombocytopaenia is gratifying, this does not imply that pulmonary oedema is caused by thrombocytopaenia. Indeed this is almost certainly a false correlation due to the underlying mechanism of septic shock which causes both pulmonary changes and D.I.C. However, it does prove that it is possible to correlate the appearances of a chest radiograph with more simple biochemical or clinical measurements. There is ample experimental evidence to suggest that microemboli are not the major cause of pulmonary changes (Ollson, 1972). It is not known whether disseminated intravascular coagulation is a coexistent phenomenon of endotoxaemia or whether it plays an important role in initiating pulmonary changes, possibly by causing increased permeability of endothelium and basement membranes. Involvement of the lower zones in all our patients who had parenchymal changes is puzzling. The absence of upper lobe diversion and the presence of normal CVP and ECG findings suggest that it is not due to left heart failure. Surfactant, which is composed basically of three phospholipids, is produced by the granular pneumocytes. The phospholipids are not manufactured by these alveolar cells and so have to be transported via the blood stream. As blood flows preferentially to the lower zones, then these regions will be affected by microemboli in D.I.C. This may lead to impairment of surfactant mechanisms and microatelectasis. Indeed, histological examination shows widespread microatelectasis and fibrinous intra-alveolar membranes in addition to pulmonary oedema. These pathological changes, which resemble the respiratory distress syndrome rather than simple
THE PULMONARY MANIFESTATIONS OF SEPTIC SHOCK
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pulmonary congestion, help to explain why the oedema of the 'shock lung' syndrome will not respond to conventional therapy. RADIOLOGICAL DIFFERENTIAL DIAGNOSIS As septic 'shock lung' frequently occurs in the post-operative period, the differential diagnosis will include cardiac failure, fluid overload, aspiration, infarction, pulmonary oxygen toxicity and infection, including that due to Pseudomonas aeruginosa. A logical approach to the diagnosis requires consideration of the following points.
Fig. 3
(A.L.)Fulminating septic shock lung.
Fig. 4 (a, b) - (JAM.) Pulmonary venous hypertension superimposed upon seplic shock lung.
1. Pulmonary shadowing which does not predominantly involve the basal regions of the lung is unlikely to be due to septic shock. 2. Conditions with predominant basal involvement which do not exhibit interstitial oedema are unlikely to be due to septic shock. 3. Although septic shock causes pulmonary shadowing and interstitial pulmonary oedema it does not, unlike cardiac failure or fluid overload, cause redistribution of blood to the upper zones.
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A l t h o u g h t h e diagnosis o f septic s h o c k is usually e s t a b l i s h e d b y h a e m a t o l o g i c a l findings the radiological a p p e a r a n c e s are still i m p o r t a n t b e c a u s e o f t h e c o m p l e x i t y o f t h e changes w h i c h occur. F o r e x a m p l e , o n c e t h e clinical diagnosis is e s t a b l i s h e d , s u b s e q u e n t r e d i s t r i b u t i o n o f b l o o d to t h e u p p e r z o n e s w o u l d suggest left v e n t r i c u l a r failure i n a d d i t i o n t o t h e 'shock lung' syndrome. N o n e o f o u r p a t i e n t s was o n s u f f i c i e n t l y h i g h concentrations of oxygen long enough to produce p u l m o n a r y o x y g e n t o x i c i t y , w h o s e radiological a p p e a r a n c e s are u n l i k e t h e ' s h o c k lung' s y n d r o m e . Similarly, n o n e o f o u r p a t i e n t s s u f f e r e d f r o m P s e u d o r n o n a s a e r u g i n o s a i n f e c t i o n , w h i c h can cause n o t o n l y p u l m o n a r y i n f e c t i o n b u t also e n d o t o x i c ' s h o c k lung'. ILLUSTRATIVE CASES Case 1. - Mrs A.L., a previously healthy 26 year old woman was admitted with a septic abortion. She was being given a slow transfusion to replace blood loss when she
collapsed. Given only this information and the chest radiograph (Fig. 3), the radiologist might conclude that pulmonary oedema was due to over-transfusion. However, knowing that the patient was collapsed, with a positive blood culture for coliform organisms, a central venous pressure of only 19 cm H 2 0 (on IPPV) and a platelet count of 30 000/cm 3, he should consider the diagnosis of endotoxic shock lung syndrome. Case 2. - J.M. was recovering from an anterior resection of the colon when his condition deteriorated. Blood pressure was 60/40 and his CVP was 10 cm H20. His platelet count was only 95 000/cm 3. The first chest radiograph (Fig. 4a) is almost within normal limits. However, careful inspection of the hila reveals less than normally distinct vessels and bronchi. This indicates minimal perihilar interstitial oedema but there is no redistribution of blood to the upper zones. He was treated with conventional therapy and transfusion and was making a good recovery when he became acutely dyspnoeic and again collapsed. On this occasion his central venous pressure had risen to 20 cm H20. A repeat platelet count was almost within normal limits. The chest radiograph (Fig. 4b) showed pulmonary oedema with redistribution of blood to the upper zones. These appearances are due to fluid overload superimposed on the 'shock lung' syndrome.
Fig. 5 (a, b) - (F.O.) Response of septic shock lung to intravenous fluids.
THE P U L M O N A R Y M A N I F E S T A T I O N S OF SEPTIC SHOCK Case 3. - F.O., aged 54, was admitted to the medical ward with septic cholangitis and endotoxic shock. He exhibited the usual features of shock and had a positive blood culture of coliform organisms and evidence of thrombocytopaenia. The chest radiograph (Fig, 5a) shows moderate interstitial pulmonary oedema with perihilar cuffing and
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some basal pulmonary shadowing. The second film (Fig. 5b) was taken only 36 h later but in the intervening period the patient was transfused with some 28 pints of fluid. Interstitial pulmonary oedema has cleared which emphasises that the management of 'shock lung' syndrome is the reverse of that of heart failure or fluid overload.
Fig. 6 (a, b) - (S.K.) Development of septic shock lung and thromobocytopaenia despite 'apparent' clinical improvement.
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Case 4, - Mrs S.K., aged 68, was recovering from an abdomino-perineal resection of the rectum when she collapsed. She was only mildly hypotensive but the platelet count was reduced to 100 000/cm 3 and the central venous pressure was 17 cm H20. A chest radiograph (Fig, 6a) revealed clear lung fields. She was treated with conventional therapy including transfusion and despite clinical improvement and a normal blood pressure, pulmonary oedema developed over the next few days. The subsequent chest radiograph (Fig. 6b) was taken when the platelet count had fallen to 30 000]cm 3. There is extensive pulmonary oedema but the central venous pressure is only 14 cm H20. This illustrates that the patient's shocked state can be quickly controlled although thrombocytopaenia and pulmonary oedema may persist for several more days. Acknowledgements. - We gratefully acknowledge the skills of the medical and nursing staff of the Intensive Therapy Unit at the Western Infirmary, Glasgow; of Mr G. Donald and the photographic staff of the University of Glasgow and of the radiographers and clerical staff of tile Department of Radiodiagnosis, the Western Infirmary, Glasgow.
REFERENCES Davis, R. B., Meeker, W. R., Jr & Bailey, W. L. (1961). Serotonin release by bacterial endotoxin. Proceedings o f the Society of Experimental Biology and Medicine, 108, 774-776. Bredenberg, C. D., James, P. M., Collins, J., Anderson, R. W.,
Martin, A. M., Jr & Hardaway, R. M. (1969). Respiratory failure in shock. Annals o f Surgery, 169, 392-403. Hinshaw, L. B., Greenfield, L. J., Owen, S. E., Black, M. R. & Guenter, C. A. (1972). Precipitation of cardiac failure in endotoxin shock. Surgery, Gynaecology and Obstetrics, 135, 39-48. Joffe, N. (1970). Roentgenologic findings in post-shock and post-operative pulmonary insufficiency. Radiology, 94, 369-375. Ledingham, I. McA., McCardle, C. S., Fisher, W. D., Maddern, M., Lees, N. W., MacDonald, J. A. E., Waddell, G. D., Milligan, G. R., Mellon, A. E. & Scott, P. D. 1L (1975). Septic shock: a three year prospective trial. Scientific Abstracts: 1st World Congress on Intensive Care, ed. I. McA. Ledingham, Publisher Bell & Bain Limited, Glasgow. Lillehei, R. C., Longerbeam, J. K., Bloch, J. H. & Manax, W. G. (1964). Nature of irreversible shock. Experimental and clinical observations. Annals o f Surgery, 160, 682-710. Ollson, P. (1972). Effects of disseminated intravascular coagulation on pulmonary circulation and respiration. International Anaesthesiology Clinics, ed. Norlander, O., pp. 173-179. Elsevier Publishing Company Limited, Amsterdam and New York. Putman, C. E., Minagi, H. & Blaisdell, F. W. (1973). The roentgen appearance of disseminated intravascular coagulation (D.I.C.), Radiology, 109, 13-18. Spink, W. W. (1962). Endotoxin shock. Annals o f Internal Medicine, 57, 538-552. Thai, A. P. & Wilson, R. F. (1965). Shock. In Current Problems in Surgery. Year Book Medical Publishers Incorporated, Chicago.
