SHORT COMMUNICATION
Serum Albumin as a Biomarker of Capillary Leak in Scuba Divers with Neurological Decompression Sickness Emmanuel Gempp, Sebastien De Maistre, and Pierre Louge GEMPP E, DE MAISTRE S, LOUGE P. Serum albumin as a biomarker hypotension with plasma volume deficit have been reof capillary leak in scuba divers with neurological decompression ported in the setting of scuba diving (7,11) or hyperbaric sickness. Aviat Space Environ Med 2014; 85:1049–52. exposure in dry conditions (2,4). However, to our knowlBackground: Prior reports have shown that decompression sickness edge, only one paper focused on the changes in serum (DCS) in scuba divers is accompanied by vascular endothelium damage attributed to gas emboli formation, resulting in capillary leak with hemoalbumin, known as the chief contributor of oncotic presconcentration. The significance of serum albumin as a biomarker of vassure maintaining fluid balance across capillaries, in the cular permeability in this condition has been insuffi ciently investigated. Delivered by Ingentapathogenesis to: jacob busch of post-decompression shock (7). In the We studied whether there was a relationship low serum On: albu-Tue, 12 Jul 2016 21:52:47 IP:between 5.101.220.158 current study, we hypothesized in a large series of recremin values on admission and the occurrence of neurological DCS. Copyright: Aerospace Medical Association Methods: Demographic, diving, and laboratory data of 52 randomly ational divers that lower serum albumin levels were selected DCS divers were compared with those of 52 asymptomatic divmore associated with the development of neurological ers referred for inadequate decompression. The diagnostic performance DCS. We also aimed to examine the diagnostic perforof serum albumin in predicting neurological DCS was assessed. Results: mance of this biomarker. Both groups did not differ from the variables examined. Serum albumin was significantly lower in injured divers than in controls (38.7 6 3 g z L21 vs. 41 6 2.9 g z L21). At a cut-off value of 35.2 g z L21, we found a specificity METHODS of 98% (95% CI 90–100) and a sensitivity of 16% (95% CI 7–28) for the Subjects prediction of neurological DCS development. Conclusion: Our findings suggest that hypoalbuminemia at initial presentation, albeit rare, accuBetween January 2012 and September 2013, 104 recrerately predicts the occurrence of neurological DCS in scuba divers. The ational diving victims of neurological DCS were admitprognostic value of this biomarker and the potential beneficial role of albumin infusion in more severe cases remain to be investigated. ted to our hyperbaric facility (Toulon, France). For the Keywords: diving, decompression sickness, serum albumin, capillary purposes of this study, the clinical diagnosis was based leak.
N
EUROLOGICAL decompression sickness (DCS) is an acute but rare disorder encountered by scuba divers, leading to incomplete recovery with potential permanent disability in 20–30% of patients (6). It is commonly accepted that this pathological condition is induced by vascular gas emboli which damage the central nervous system by several mechanisms, including occlusion of capillary blood flow, intravascular coagulation, and systemic inflammatory response resulting mainly from endothelial dysfunction and leukocyte activation (1). Numerous studies involving different animal models have experimentally shown that there was an increased permeability of the blood-brain barrier, but also the jugular veins and carotid arteries following DCS or direct infusion of air bubbles into the circulation, leading to extravasation of plasma with subsequent hemoconcentration and interstitial edema (9,12,13). Elevated hematocrit levels have also been observed in human subjects who suffered from neurological DCS after diving with a potential relationship between the degree of hemoconcentration and the neurological outcome (3). In the same way, anecdotal cases of severe
on the presence of symptoms indicative of central nervous system (CNS) impairment (paresthesias, numbness, motor weakness, ataxia, bladder dysfunction, altered higher function or speech, visual disturbance) and inner ear disorders (vertigo, tinnitus, hearing loss) recognized within 6 h following a scuba dive. Clinical and biological variables were collected and maintained prospectively in a standardized database and analyzed retrospectively. Exclusion criteria applied during the enrollment were as follows: 1) cases suspected of cerebral arterial gas embolism; 2) patients with ambiguous presentation; 3) initial admission more than 6 h after onset of symptoms; and 4) a history of liver or renal failure and acute sepsis that could interfere with plasma albumin concentrations. Among the 82 patients eligible for the study, 52 cases
From the Department of Diving and Hyperbaric Medicine, Sainte Anne’s Military Hospital, Toulon Cedex, France. This manuscript was received for review in May 2014. It was accepted for publication in July 2014. Address correspondence and reprint requests to: Emmanuel Gempp, Department of Diving and Hyperbaric Medicine, Sainte Anne’s Military Hospital, BP 600, 83800 Toulon Cedex 9, France; [email protected]. Reprint & Copyright © by the Aerospace Medical Association, Alexandria, VA. DOI: 10.3357/ASEM.4069.2014
Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
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SERUM ALBUMIN & DCS—GEMPP ET AL. were then randomly selected for comparison with 52 control divers. This control group consisted of asymptomatic divers referred for inadequate decompression (i.e., fast ascent, omitted decompression stops) during the same period who met none of the exclusion criteria used in the selection of the DCS patients and who were comparable in terms of age and sex. Diving parameters, fluid loading after diving, and delay between blood collection and dive completion were recorded in each group. The study protocol was approved by the local ethics committee (Sainte Anne’s Military Hospital, France) and all patients gave their written informed consent to participate. Procedure
TABLE II. CHARACTERISTICS OF THE DIVERS ENROLLED IN THE STUDY. Variables
DCS Divers (N 5 52)
Controls (N 5 52)
Age (yr) 48 6 9 45 6 13 Male sex 21% 11% Diving depth (msw) 42 6 10 42 6 13 Total dive time (min) 36 6 8 33 6 12 Repetitive dive 19% 10% Delay for blood collection (min) 120 [60–300] 150 [60–270] Fluid loading after diving (ml) 500 [0–3000] 300 [0–1500] Hematocrit (%) 44.5 6 4.4 43.6 6 2.2
P-Value 0.14 0.39 0.99 0.14 0.9 0.18 0.31 0.22
Data are presented as means 6 SD, or median [range], or percentages of presented cases. Note that all divers were rehydrated orally except for two DCS divers in whom fluid loading was administered with normal saline infusion.
Blood samples were taken from the antecubital vein of all divers at the time of initial presentation and then no significant differences in diving parameter, delay of immediately centrifuged for measurement of serum albucollection of blood, or hydration status expressed by the min with an immunoturbinimetric assay kit (Cobas autoamount of fluid loading and hematocrit levels. Serum analyzer, Roche diagnostics), for which normal range albumin values were lower in the group of injured divvalues are 35-52 g z L21 according to the manufacturer. ers than in the control group (38.7 6 3 g z L21 vs. 41 6 Hematocrit levels were also determinedDelivered by the standard by Ingenta2.9 to:gjacob z L21,busch P 5 0.0002) (Fig. 1). Two DCS divers exhibtechnique for controlling potentialIP: hemodilution. 5.101.220.158 On: Tue,ited 12 albumin Jul 2016 levels 21:52:47 ⱕ 30 g z L21, including one that had Copyright: Aerospace Medical Association a transient hemodynamic collapse which required fluid Statistical Analysis challenge with colloid and albumin infusion 6 h followData were expressed as mean 6 SD or median with ing admission. range for nonparametric variables. Differences between Fig. 2 shows a scatter plot of serum albumin in relagroups were compared using the unpaired Student’s tion with pre-evaluation fluid volume for each group t-test or the Mann–Whitney U-test where appropriate. that disclaims the possibility that hemodilution may be Associations between categorical variables were meathe cause for the decrease in serum albumin in DCS pasured by the Fisher exact test. A receiver operating chartients. The diagnostic performance of serum albumin in acteristics curve with the corresponding area under the predicting neurological DCS was moderate with an area curve was performed to discriminate the lowest meaunder the curve of 71% (95%CI 61-81) (Fig. 3). The level surement of serum albumin levels in predicting neurowith the highest specificity and sensitivity was 40 g z L21 logical DCS development, and specificity with sensitivity (specificity 5 69%, 95% CI 54–81; sensitivity 5 67%, 95% was obtained with the use of predefined thresholds. CI 53–80). A cutoff value of 35.2 g z L21 was able to preOdds ratio with 95% confidence intervals (CI) were caldict DCS development with specificity of 98% (95% CI culated when needed and P-values lower than 0.05 were 90–100) and a sensitivity of 16% (95% CI 7–28). We idenconsidered significant. Statistical calculations were pertified a strong association between hypoalbuminemia formed with Graphpad Prism 5.00 (GraphPad Software, set below this cutoff point and the occurrence of neuroSan Diego, CA). logical DCS (OR 5 3.9, 95% CI 1.7–8.8, P 5 0.0017). RESULTS CNS disorders with a predominantly spinal distribution were present in 33 injured divers (Table I), while 19 patients had clinical manifestations of inner ear DCS, including 3 with a combination of symptoms. Baseline characteristics and laboratory findings of DCS patients and controls are shown in Table II. There were TABLE I. DISTRIBUTION OF DCS DIVERS WITH CNS SYMPTOMS AT INITIAL PRESENTATION. Initial Presentation
N
Subjective sensory abnormalities only 17 Objective sensory loss and/or mild motor impairment 6 Severe presentation with sensory, motor, and sphincter dysfunction 7 Cerebral involvement (speech, visual, or cognitive 3 function alterations)
1050
Fig. 1. Distribution of individual values of serum albumin between the two groups of divers. Bars are mean 6 SEM.
Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
SERUM ALBUMIN & DCS—GEMPP ET AL. hypoalbuminemia of 18 g z L21 and hematocrit of 58% (7). Observations of injured divers with major plasma volume contraction and severe hemoconcentration following simulated diving experiments (4), compressed air work (2), or surface supplied air diving (11) had previously been described, but the measurement of serum albumin was not determined at that time. Previous clinical work has shown that patients with hematocrit values ⱖ 48% were more likely to have neurological deficits, although this biomarker did not correlate with the overall risk for developing neurological DCS (3). In this series, hematocrit was not different between groups though it would be expected to be higher in the one of the injured divers. This relative dissociation with the decrease in serum albumin may be explained by the fact that early measurements of hematocrit do not reflect Fig. 2. Distribution of individual values of serum albumin vs. volume of fluid loading after diving for DCS divers (black symbols) and controls steady-state values and that equilibration of hemato(gray symbols). crit occurs later than changes in serum albumin. Elevated hematocrit at initial presentation would be present only in cases of significant hypoalbuminemia DISCUSSION or dehydration. The present study has demonstrated a significant deInterestingly, the current data included another case bywith Ingentaof to:a jacob crease in serum albumin levels in diversDelivered presenting scuba busch diver presenting with neurological symptoms IP: 5.101.220.158 On: Tue, 12 Jul 2016 21:52:47 neurological manifestations of DCS as compared to asinvolving the spinal cord in which the general condition Copyright: Association ymptomatic divers who had performed a dive Aerospace with in- Medical worsened several hours after initial evaluation, with deadequate decompression. Early investigations during veloping hemodynamic collapse that resolved promptly the 1970s with deep divers breathing gas mixtures with after fluid challenge. This case reinforces the notion that, helium-oxygen have reported changes in serum proteins even if this event is rare, it should not be ignored, but in association with various compression-decompression watched for by systematically controlling blood presprofiles, but the results were conflicting and difficult to sure and determining hematocrit combined with serum interpret (15). albumin during hospitalization. Our findings suggest that DCS is responsible for capA large number of experimental studies seem to agree illary leakage with albumin loss from the vessels to the on the fact that disturbance of vascular permeability interstitial space after controlling for other potential with extravasation of plasma is critical in the developcauses of hypoalbuminemia, including dilution, liver ment of neurological DCS (9,12,13). The causative agent and renal diseases, malabsorption, or increased catabomay be circulating bubbles formed during decompreslism. This result is unique but consistent with a recent sion that disrupt the endothelial wall (14) and interact case of severe hypovolemic shock with clinical signs of with blood components (platelets and leukocytes, paranasarca complicating an inner ear DCS after scuba ticularly) (13,15), but the exact mechanisms implicated diving for which laboratory investigations revealed in the capillary hyperpermeability and barrier breakdown during DCS are not clear. Literature on more common clinical scenarios such as sepsis, chemotherapy toxicity, or even allergy reaction suggests that the pathway for the transcapillary transport of albumin in this condition may be through intercellular junctions and/or vesicular transfer (i.e., caveolae) (8). Several biochemical agents appear to be contributors to this process, including inflammatory mediators such as interleukins (IL-1, IL-6), TNFa, histamine, thrombin, bradykinin, and platelet activating factor (5), but also factors altering the endothelial barrier stability such as vascular endothelial growth factor, nitrite oxide, and angiopoietin (8). Complement activation may be also involved in microbubbleinduced microvascular permeability alteration, as was established by Huang and Lin in a study using an animal model of air embolism (10). We found that serum albumin is a specific biomarker which allows ruling in the diagnosis of neurological Fig. 3. Receiver operating curve of serum albumin in predicting neurologiDCS with very good reliability when the values are less cal decompression sickness in scuba divers. The area under the curve is 71% than 35.2 g z L21, and it is noteworthy that this cutoff (P , 0.0002). The grey diagonal line represents the line of no discrimination. Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
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SERUM ALBUMIN & DCS—GEMPP ET AL. REFERENCES value is quite similar to that recognized as the threshold 1. Barak M, Katz Y. Microbubble: pathophysiology and clinical reference by most laboratories for determining hypoalimplications. Chest 2005; 128:2918–32. 21 buminemia (i.e., 35 g z L ). However, we must admit 2. Barnard EE, Hanson JM, Rowton-Lee MA, Morgan AG, Polak A. Post-decompression shock due to extravasation of plasma. that the clinical usefulness of this test is hampered by its BMJ 1966; 2:154–5. low sensitivity, meaning that a normal value does not 3. Boussuges A, Blanc P, Molenat F, Bergmann E, Sainty JM. Haemonecessarily rule out the occurrence of neurological DCS. concentration in neurological decompression illness. Int J Additional work is needed to assess the prognostic value Sports Med 1996; 17:351–5. 4. Brunner FP, Frick PG, Bühlmann AA. Post-decompression shock and the dynamic changes of this biomarker during the due to extravasation of plasma. Lancet 1964; 1:1071–3. first 24 h of initial presentation. 5. Fishel RS, Are S, Barbul A. Vessel injury and capillary leak. Crit A potential weakness of this study is the influence Care Med 2003; 31:S502–11. of fluid loading after diving that may have contributed 6. Gempp E, Blatteau JE. Risk factors and treatment outcome in scuba divers with spinal cord decompression sickness. J Crit to some hemodilution with subsequent alterations in Care 2010; 25:236–42. serum albumin levels for both groups. This condition 7. Gempp E, Lacroix G, Cournac JM, Louge P. Severe capillary could lead to an under-estimation of the threshold value leak syndrome after inner ear decompression sickness in a recreational scuba diver. J Emerg Med 2013; 45:70–3. found here, hence making the clinical applicability and 8. Goddard LM, Iruela-Arispe ML. Cellular and molecular regulation the generalization of our results for determining the diof vascular permeability. Thromb Haemost 2013; 109:407–15. agnosis of neurological DCS difficult. 9. Hills BA, James PB. Microbubble damage to the blood-brain In conclusion, the study reveals for the first time that barrier: relevance to decompression sickness. Undersea Biomed Res 1991; 18:111–6. scuba divers with neurological DCS have lower serum 10. Huang KL, Lin YC. Activation of complement and neutrophils albumin levels than asymptomatic divers who had perincreases vascular permeability during air embolism. Aviat formed dives with inadequate decompression, suggestSpace Environ Med 1997; 68:300–5. 11. Kondo Y, Shiohira S, Kamizato K, Teruya K, Fuchigami T, et al. ing a diffuse capillary leak resulting from endothelial by Ingenta to: jacob busch Vascular hyperpermeability in pulmonary decompression illness: dysfunction in the pathogenesis of thisDelivered disease. Albeit IP: 5.101.220.158 On: Tue, 12 Jul 21:52:47 'the2016 chokes' . Emerg Med Australas 2012; 24:460–2. this condition is uncommon, serum Copyright: albumin with val12. Lehtosalo J, Panula P, Laitinen LA. The permeability alteration of Aerospace Medical Association 21 ues below 35.2 g z L early on admission accurately brain and spinal cord vasculature to horseradish peroxidase during experimental decompression sickness as compared predicts the development of neurological DCS. The relito the alteration in permeability induced by hyperosmolar ability of albumin infusion as fluid replacement in case solution. Acta Neuropathol 1982; 57:179–87. of significant hypoalbuminemia should be examined in 13. Levin LL, Stewart GJ, Lynch PR, Bove AA. Blood and blood vessel further studies. wall changes induced by decompression sickness in dogs. J ACKNOWLEDGMENT Authors and affiliation: Emmanuel Gempp, M.D., Sebastien De Maistre, M.D., and Pierre Louge, M.D., Department of Diving and Hyperbaric Medicine, Sainte Anne's Military Hospital, French Armed Forces Health Service, Toulon Cedex, France.
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Appl Physiol Respir Environ Exerc Physiol 1981; 50:944–9. 14. Nossum V, Koteng S, Brubakk AO. Endothelial damage by bubbles in the pulmonary artery of the pig. Undersea Hyperb Med 1999; 26:1–8. 15. Philp RB. A review of blood changes associated with compressiondecompression: relationship to decompression sickness. Undersea Biomed Res 1974; 1:117–50.
Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
Serum Albumin as a Biomarker of Capillary Leak in Scuba Divers with Neurological Decompression Sickness Emmanuel Gempp, Sebastien De Maistre, and Pierre Louge GEMPP E, DE MAISTRE S, LOUGE P. Serum albumin as a biomarker hypotension with plasma volume deficit have been reof capillary leak in scuba divers with neurological decompression ported in the setting of scuba diving (7,11) or hyperbaric sickness. Aviat Space Environ Med 2014; 85:1049–52. exposure in dry conditions (2,4). However, to our knowlBackground: Prior reports have shown that decompression sickness edge, only one paper focused on the changes in serum (DCS) in scuba divers is accompanied by vascular endothelium damage attributed to gas emboli formation, resulting in capillary leak with hemoalbumin, known as the chief contributor of oncotic presconcentration. The significance of serum albumin as a biomarker of vassure maintaining fluid balance across capillaries, in the cular permeability in this condition has been insuffi ciently investigated. Delivered by Ingentapathogenesis to: jacob busch of post-decompression shock (7). In the We studied whether there was a relationship low serum On: albu-Tue, 12 Jul 2016 21:52:47 IP:between 5.101.220.158 current study, we hypothesized in a large series of recremin values on admission and the occurrence of neurological DCS. Copyright: Aerospace Medical Association Methods: Demographic, diving, and laboratory data of 52 randomly ational divers that lower serum albumin levels were selected DCS divers were compared with those of 52 asymptomatic divmore associated with the development of neurological ers referred for inadequate decompression. The diagnostic performance DCS. We also aimed to examine the diagnostic perforof serum albumin in predicting neurological DCS was assessed. Results: mance of this biomarker. Both groups did not differ from the variables examined. Serum albumin was significantly lower in injured divers than in controls (38.7 6 3 g z L21 vs. 41 6 2.9 g z L21). At a cut-off value of 35.2 g z L21, we found a specificity METHODS of 98% (95% CI 90–100) and a sensitivity of 16% (95% CI 7–28) for the Subjects prediction of neurological DCS development. Conclusion: Our findings suggest that hypoalbuminemia at initial presentation, albeit rare, accuBetween January 2012 and September 2013, 104 recrerately predicts the occurrence of neurological DCS in scuba divers. The ational diving victims of neurological DCS were admitprognostic value of this biomarker and the potential beneficial role of albumin infusion in more severe cases remain to be investigated. ted to our hyperbaric facility (Toulon, France). For the Keywords: diving, decompression sickness, serum albumin, capillary purposes of this study, the clinical diagnosis was based leak.
N
EUROLOGICAL decompression sickness (DCS) is an acute but rare disorder encountered by scuba divers, leading to incomplete recovery with potential permanent disability in 20–30% of patients (6). It is commonly accepted that this pathological condition is induced by vascular gas emboli which damage the central nervous system by several mechanisms, including occlusion of capillary blood flow, intravascular coagulation, and systemic inflammatory response resulting mainly from endothelial dysfunction and leukocyte activation (1). Numerous studies involving different animal models have experimentally shown that there was an increased permeability of the blood-brain barrier, but also the jugular veins and carotid arteries following DCS or direct infusion of air bubbles into the circulation, leading to extravasation of plasma with subsequent hemoconcentration and interstitial edema (9,12,13). Elevated hematocrit levels have also been observed in human subjects who suffered from neurological DCS after diving with a potential relationship between the degree of hemoconcentration and the neurological outcome (3). In the same way, anecdotal cases of severe
on the presence of symptoms indicative of central nervous system (CNS) impairment (paresthesias, numbness, motor weakness, ataxia, bladder dysfunction, altered higher function or speech, visual disturbance) and inner ear disorders (vertigo, tinnitus, hearing loss) recognized within 6 h following a scuba dive. Clinical and biological variables were collected and maintained prospectively in a standardized database and analyzed retrospectively. Exclusion criteria applied during the enrollment were as follows: 1) cases suspected of cerebral arterial gas embolism; 2) patients with ambiguous presentation; 3) initial admission more than 6 h after onset of symptoms; and 4) a history of liver or renal failure and acute sepsis that could interfere with plasma albumin concentrations. Among the 82 patients eligible for the study, 52 cases
From the Department of Diving and Hyperbaric Medicine, Sainte Anne’s Military Hospital, Toulon Cedex, France. This manuscript was received for review in May 2014. It was accepted for publication in July 2014. Address correspondence and reprint requests to: Emmanuel Gempp, Department of Diving and Hyperbaric Medicine, Sainte Anne’s Military Hospital, BP 600, 83800 Toulon Cedex 9, France; [email protected]. Reprint & Copyright © by the Aerospace Medical Association, Alexandria, VA. DOI: 10.3357/ASEM.4069.2014
Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
1049
SERUM ALBUMIN & DCS—GEMPP ET AL. were then randomly selected for comparison with 52 control divers. This control group consisted of asymptomatic divers referred for inadequate decompression (i.e., fast ascent, omitted decompression stops) during the same period who met none of the exclusion criteria used in the selection of the DCS patients and who were comparable in terms of age and sex. Diving parameters, fluid loading after diving, and delay between blood collection and dive completion were recorded in each group. The study protocol was approved by the local ethics committee (Sainte Anne’s Military Hospital, France) and all patients gave their written informed consent to participate. Procedure
TABLE II. CHARACTERISTICS OF THE DIVERS ENROLLED IN THE STUDY. Variables
DCS Divers (N 5 52)
Controls (N 5 52)
Age (yr) 48 6 9 45 6 13 Male sex 21% 11% Diving depth (msw) 42 6 10 42 6 13 Total dive time (min) 36 6 8 33 6 12 Repetitive dive 19% 10% Delay for blood collection (min) 120 [60–300] 150 [60–270] Fluid loading after diving (ml) 500 [0–3000] 300 [0–1500] Hematocrit (%) 44.5 6 4.4 43.6 6 2.2
P-Value 0.14 0.39 0.99 0.14 0.9 0.18 0.31 0.22
Data are presented as means 6 SD, or median [range], or percentages of presented cases. Note that all divers were rehydrated orally except for two DCS divers in whom fluid loading was administered with normal saline infusion.
Blood samples were taken from the antecubital vein of all divers at the time of initial presentation and then no significant differences in diving parameter, delay of immediately centrifuged for measurement of serum albucollection of blood, or hydration status expressed by the min with an immunoturbinimetric assay kit (Cobas autoamount of fluid loading and hematocrit levels. Serum analyzer, Roche diagnostics), for which normal range albumin values were lower in the group of injured divvalues are 35-52 g z L21 according to the manufacturer. ers than in the control group (38.7 6 3 g z L21 vs. 41 6 Hematocrit levels were also determinedDelivered by the standard by Ingenta2.9 to:gjacob z L21,busch P 5 0.0002) (Fig. 1). Two DCS divers exhibtechnique for controlling potentialIP: hemodilution. 5.101.220.158 On: Tue,ited 12 albumin Jul 2016 levels 21:52:47 ⱕ 30 g z L21, including one that had Copyright: Aerospace Medical Association a transient hemodynamic collapse which required fluid Statistical Analysis challenge with colloid and albumin infusion 6 h followData were expressed as mean 6 SD or median with ing admission. range for nonparametric variables. Differences between Fig. 2 shows a scatter plot of serum albumin in relagroups were compared using the unpaired Student’s tion with pre-evaluation fluid volume for each group t-test or the Mann–Whitney U-test where appropriate. that disclaims the possibility that hemodilution may be Associations between categorical variables were meathe cause for the decrease in serum albumin in DCS pasured by the Fisher exact test. A receiver operating chartients. The diagnostic performance of serum albumin in acteristics curve with the corresponding area under the predicting neurological DCS was moderate with an area curve was performed to discriminate the lowest meaunder the curve of 71% (95%CI 61-81) (Fig. 3). The level surement of serum albumin levels in predicting neurowith the highest specificity and sensitivity was 40 g z L21 logical DCS development, and specificity with sensitivity (specificity 5 69%, 95% CI 54–81; sensitivity 5 67%, 95% was obtained with the use of predefined thresholds. CI 53–80). A cutoff value of 35.2 g z L21 was able to preOdds ratio with 95% confidence intervals (CI) were caldict DCS development with specificity of 98% (95% CI culated when needed and P-values lower than 0.05 were 90–100) and a sensitivity of 16% (95% CI 7–28). We idenconsidered significant. Statistical calculations were pertified a strong association between hypoalbuminemia formed with Graphpad Prism 5.00 (GraphPad Software, set below this cutoff point and the occurrence of neuroSan Diego, CA). logical DCS (OR 5 3.9, 95% CI 1.7–8.8, P 5 0.0017). RESULTS CNS disorders with a predominantly spinal distribution were present in 33 injured divers (Table I), while 19 patients had clinical manifestations of inner ear DCS, including 3 with a combination of symptoms. Baseline characteristics and laboratory findings of DCS patients and controls are shown in Table II. There were TABLE I. DISTRIBUTION OF DCS DIVERS WITH CNS SYMPTOMS AT INITIAL PRESENTATION. Initial Presentation
N
Subjective sensory abnormalities only 17 Objective sensory loss and/or mild motor impairment 6 Severe presentation with sensory, motor, and sphincter dysfunction 7 Cerebral involvement (speech, visual, or cognitive 3 function alterations)
1050
Fig. 1. Distribution of individual values of serum albumin between the two groups of divers. Bars are mean 6 SEM.
Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
SERUM ALBUMIN & DCS—GEMPP ET AL. hypoalbuminemia of 18 g z L21 and hematocrit of 58% (7). Observations of injured divers with major plasma volume contraction and severe hemoconcentration following simulated diving experiments (4), compressed air work (2), or surface supplied air diving (11) had previously been described, but the measurement of serum albumin was not determined at that time. Previous clinical work has shown that patients with hematocrit values ⱖ 48% were more likely to have neurological deficits, although this biomarker did not correlate with the overall risk for developing neurological DCS (3). In this series, hematocrit was not different between groups though it would be expected to be higher in the one of the injured divers. This relative dissociation with the decrease in serum albumin may be explained by the fact that early measurements of hematocrit do not reflect Fig. 2. Distribution of individual values of serum albumin vs. volume of fluid loading after diving for DCS divers (black symbols) and controls steady-state values and that equilibration of hemato(gray symbols). crit occurs later than changes in serum albumin. Elevated hematocrit at initial presentation would be present only in cases of significant hypoalbuminemia DISCUSSION or dehydration. The present study has demonstrated a significant deInterestingly, the current data included another case bywith Ingentaof to:a jacob crease in serum albumin levels in diversDelivered presenting scuba busch diver presenting with neurological symptoms IP: 5.101.220.158 On: Tue, 12 Jul 2016 21:52:47 neurological manifestations of DCS as compared to asinvolving the spinal cord in which the general condition Copyright: Association ymptomatic divers who had performed a dive Aerospace with in- Medical worsened several hours after initial evaluation, with deadequate decompression. Early investigations during veloping hemodynamic collapse that resolved promptly the 1970s with deep divers breathing gas mixtures with after fluid challenge. This case reinforces the notion that, helium-oxygen have reported changes in serum proteins even if this event is rare, it should not be ignored, but in association with various compression-decompression watched for by systematically controlling blood presprofiles, but the results were conflicting and difficult to sure and determining hematocrit combined with serum interpret (15). albumin during hospitalization. Our findings suggest that DCS is responsible for capA large number of experimental studies seem to agree illary leakage with albumin loss from the vessels to the on the fact that disturbance of vascular permeability interstitial space after controlling for other potential with extravasation of plasma is critical in the developcauses of hypoalbuminemia, including dilution, liver ment of neurological DCS (9,12,13). The causative agent and renal diseases, malabsorption, or increased catabomay be circulating bubbles formed during decompreslism. This result is unique but consistent with a recent sion that disrupt the endothelial wall (14) and interact case of severe hypovolemic shock with clinical signs of with blood components (platelets and leukocytes, paranasarca complicating an inner ear DCS after scuba ticularly) (13,15), but the exact mechanisms implicated diving for which laboratory investigations revealed in the capillary hyperpermeability and barrier breakdown during DCS are not clear. Literature on more common clinical scenarios such as sepsis, chemotherapy toxicity, or even allergy reaction suggests that the pathway for the transcapillary transport of albumin in this condition may be through intercellular junctions and/or vesicular transfer (i.e., caveolae) (8). Several biochemical agents appear to be contributors to this process, including inflammatory mediators such as interleukins (IL-1, IL-6), TNFa, histamine, thrombin, bradykinin, and platelet activating factor (5), but also factors altering the endothelial barrier stability such as vascular endothelial growth factor, nitrite oxide, and angiopoietin (8). Complement activation may be also involved in microbubbleinduced microvascular permeability alteration, as was established by Huang and Lin in a study using an animal model of air embolism (10). We found that serum albumin is a specific biomarker which allows ruling in the diagnosis of neurological Fig. 3. Receiver operating curve of serum albumin in predicting neurologiDCS with very good reliability when the values are less cal decompression sickness in scuba divers. The area under the curve is 71% than 35.2 g z L21, and it is noteworthy that this cutoff (P , 0.0002). The grey diagonal line represents the line of no discrimination. Aviation, Space, and Environmental Medicine x Vol. 85, No. 10 x October 2014
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SERUM ALBUMIN & DCS—GEMPP ET AL. REFERENCES value is quite similar to that recognized as the threshold 1. Barak M, Katz Y. Microbubble: pathophysiology and clinical reference by most laboratories for determining hypoalimplications. Chest 2005; 128:2918–32. 21 buminemia (i.e., 35 g z L ). However, we must admit 2. Barnard EE, Hanson JM, Rowton-Lee MA, Morgan AG, Polak A. Post-decompression shock due to extravasation of plasma. that the clinical usefulness of this test is hampered by its BMJ 1966; 2:154–5. low sensitivity, meaning that a normal value does not 3. Boussuges A, Blanc P, Molenat F, Bergmann E, Sainty JM. Haemonecessarily rule out the occurrence of neurological DCS. concentration in neurological decompression illness. Int J Additional work is needed to assess the prognostic value Sports Med 1996; 17:351–5. 4. Brunner FP, Frick PG, Bühlmann AA. Post-decompression shock and the dynamic changes of this biomarker during the due to extravasation of plasma. Lancet 1964; 1:1071–3. first 24 h of initial presentation. 5. Fishel RS, Are S, Barbul A. Vessel injury and capillary leak. Crit A potential weakness of this study is the influence Care Med 2003; 31:S502–11. of fluid loading after diving that may have contributed 6. Gempp E, Blatteau JE. Risk factors and treatment outcome in scuba divers with spinal cord decompression sickness. J Crit to some hemodilution with subsequent alterations in Care 2010; 25:236–42. serum albumin levels for both groups. This condition 7. Gempp E, Lacroix G, Cournac JM, Louge P. Severe capillary could lead to an under-estimation of the threshold value leak syndrome after inner ear decompression sickness in a recreational scuba diver. J Emerg Med 2013; 45:70–3. found here, hence making the clinical applicability and 8. Goddard LM, Iruela-Arispe ML. Cellular and molecular regulation the generalization of our results for determining the diof vascular permeability. Thromb Haemost 2013; 109:407–15. agnosis of neurological DCS difficult. 9. Hills BA, James PB. Microbubble damage to the blood-brain In conclusion, the study reveals for the first time that barrier: relevance to decompression sickness. Undersea Biomed Res 1991; 18:111–6. scuba divers with neurological DCS have lower serum 10. Huang KL, Lin YC. Activation of complement and neutrophils albumin levels than asymptomatic divers who had perincreases vascular permeability during air embolism. Aviat formed dives with inadequate decompression, suggestSpace Environ Med 1997; 68:300–5. 11. Kondo Y, Shiohira S, Kamizato K, Teruya K, Fuchigami T, et al. ing a diffuse capillary leak resulting from endothelial by Ingenta to: jacob busch Vascular hyperpermeability in pulmonary decompression illness: dysfunction in the pathogenesis of thisDelivered disease. Albeit IP: 5.101.220.158 On: Tue, 12 Jul 21:52:47 'the2016 chokes' . Emerg Med Australas 2012; 24:460–2. this condition is uncommon, serum Copyright: albumin with val12. Lehtosalo J, Panula P, Laitinen LA. The permeability alteration of Aerospace Medical Association 21 ues below 35.2 g z L early on admission accurately brain and spinal cord vasculature to horseradish peroxidase during experimental decompression sickness as compared predicts the development of neurological DCS. The relito the alteration in permeability induced by hyperosmolar ability of albumin infusion as fluid replacement in case solution. Acta Neuropathol 1982; 57:179–87. of significant hypoalbuminemia should be examined in 13. Levin LL, Stewart GJ, Lynch PR, Bove AA. Blood and blood vessel further studies. wall changes induced by decompression sickness in dogs. J ACKNOWLEDGMENT Authors and affiliation: Emmanuel Gempp, M.D., Sebastien De Maistre, M.D., and Pierre Louge, M.D., Department of Diving and Hyperbaric Medicine, Sainte Anne's Military Hospital, French Armed Forces Health Service, Toulon Cedex, France.
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Appl Physiol Respir Environ Exerc Physiol 1981; 50:944–9. 14. Nossum V, Koteng S, Brubakk AO. Endothelial damage by bubbles in the pulmonary artery of the pig. Undersea Hyperb Med 1999; 26:1–8. 15. Philp RB. A review of blood changes associated with compressiondecompression: relationship to decompression sickness. Undersea Biomed Res 1974; 1:117–50.
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