E. Hagni Wardoyo1,2*, Devi RM Tarigan1, Ni Luh Eka Suprapti1, I Wayan Tunjung3
1Hyperbaric center Mataram City Hospital, Lombok
2Small islands medicine department, Faculty of Medicine Mataram University
3Neurology Department Mataram City Hospital, Lombok
*Corresponding author: [email protected] Abstract
Background: Cerebral arterial gas embolism (CAGE) is one of emergency situation faced by divers.
Diagnosing CAGE somehow difficult due to unspecific and may overlapping with decompression sickness type II, even in hospital setting. Diagnosing CAGE in Type II DCS may not much affect the therapy, but outcome may vary.
Case illustration: Case: A 21 year old Russian female is come to the ER of Mataram city hospital (MCH) with a chief complaint of delirium post diving. History of diving mentioned that the depth was 35 fsw, for 15 minutes, 1 hour after surfacing she felt severe headache and increasing after a half hour. She arrived at MCH 3 hours after surfacing. During transport to MCH, oxygen 100% was given only first 30 minutes then run-out.
Physical examination: patient was delirium, Vital sign was normal, Head CT-scan: cerebral edema, blood drawn: WBC 14,800/μL, Hct 52%, RBC 4.61x106 / μL. Neurologist of MCH reffer patient to Hyperbaric center with conclusion of edema of the brain with diagnosis of cerebral arterial gas embolism and type II decompression sickness. Table 6 US Navy was set. Everytime oxygen masker was on, convulsion become more prominent. Heart rate was monitored unstable during therapy. Due to uncertain condition, therapy was then terminated at minute of 20 and ICU is prepared. Patient is deceased 1 hour later during stabilization pre- ICU.
Discussion: In anamnesis, we use ‘rule of ten’ US Navy: may occur at any depth, symptoms occur less than 10 minutes after surfacing. Physical examinations: predominant of central nervous system (decrease of consciousness, convulsion, pathologic reflexes of extremities, vertigo symptoms); Head CT-scan: cerebral edema; Physiologic stress of the blood: Blood-drawn shows haemoconcentrations. Hyperbaric oxygen therapy also added value of diagnosis: CNS symptoms increasing within oxygenation. The consequences of diagnose CAGE is affect in lowering the depth of hyperbaric oxygen therapy, the necessities of sedatives pre hyperbaric, management post hyperbaric and outcome of the patient.
Conclusion: Diagnosing CAGE in hospital equipped with hyperbaric chamber is less complex than hospital not equipped with hyperbaric chamber through hyperbaric oxygen therapy response. Diagnosing CAGE is important in management and prediction of outcome.
Keyword: Cerebral arterial gas embolism, Decompression sickness, Hyperbaric oxygen therapy, Table 6 US Navy
Background
Cerebral arterial gas embolism (CAGE) in post diving occur during (rapid) ascent after breathing compressed air in the depth. CAGE is a serious dive injury causing death couples minutes to several hours after surfacing. CAGE estimated to occur in approximately 1 in 20,000 to 35,000 dives in military divers (Neuman).
Patophysiology of CAGE involve gas expands in the lungs may rupture into adjacent lung
tissue and bubbles goes on to the artery. Due to gas always search for higher space, cerebral may highly affected. CAGE may play a role as primary disease or secondary to pulmonary barotrauma or acute type II decompression illness (AA Bove, Kindwall, Neuman).
Case illustration
A Russian female, 21 years old came to ER with chief complain of convulsion after diving.
History of diving was 3 hours prior to hospital with
depth of 35 fsw, for 15 minutes, 1 hour after surfacing she felt severe headache and increasing after a half hour. Seizures - unconsciousness suddenly appear then, patient was given 100%
oxygen for more less 30 minutes and stopped due to lack of oxygen supply. Physical examination General condition: convulsion state- unconciouseness, T 130/70 mmHg, RR 30x/minutes, HR 110x/minutes, temperature 36.7°C. Convulsion type is general epileptic, tonic clonic without lateralization. Laboratory finding:
WBC 14.8 x 103/μL, Hct 52%, RBC 4.61x106 /μL, lymphocyte 2,9%, monocyt 7.1% eosinophyl 0.0%, basophyl 0.1%, neutrophil 89.9%, platelet 293 x 103 /μL. Blood gas analysis: pH 7.270, pCO2 59 mmHg, pO2 20 mmHg, Natrium 139.0 mmol/L, Kalium 4.30 mmol/L, Calcium 0.590 mmol/L.
Conclusion of head CT Scan confirmed of cerebral edema
Discussion
Recreational divers is use open circuit system commonly (SCUBA divers), due to (1) a short time training needed, (2) less complex dive instruments and (3) use compressed air tank.
CAGE is common in open circuit system diving, less common in closed circuit system.1
CAGE may affect much wider signs and symptoms than Decompression illness does, they are2,3,4: 1. Convulsion, 18-25% of convulsion from 74 diving injury with CAGE. 2. Neurological deficit. 3. Cerebral edema. This also called Type III Decompression illness.
Physiologic stress of CAGE may found in routine blood drawn. The prominent stress is haemoconcentration. The exact mechanism is unkonown, one suggest that bubbles formation intra-extravessel promote rapid production of inlamatory cells another propose relative- dehidration in diving due to heat loss or plasma leackage.5 Leucocytosis was found as high as 14.8 x 103/μL and haemotocrit raisen up to 52%. We still continue to encourage clinician for not administrate antibiotics due to this reason, especially leucocytosis with increased netrophyl band.
Diagnosing CAGE post diving that had a rapid onset after surfacing is not difficult, this is follow ‘rule of ten’ developed by US Navy is differentiate between Decompression Illness and CAGE. The rule of ten is as follow: Onset of CAGE is less than 10 minutes after surfacing, while DCS is more than 10 minutes; the depth of dive DCS is more than 10 meters sea water while CAGE may
occur at any depth.3 In addition, CAGE symptoms involved central neurologycal system while DCS had a wide range of symptoms. The fact is symptoms may overlapp to each other, there is a chance that DCS may develop CAGE soon or later.
More over the presence of cutis marmorata as a pathognomis of Type II DCS if plus with neurological deficits should be “CAGE awareness”
regardless follow ‘rule of ten’ or not.
Unconsciousness pastient in dive injury also considered as CAGE, even the anamnesis, physical and related examination did not support the diagnosis.6,7
This case is typical from developing Type II decompression Illness that is occasional proximate cause of CAGE; due to unsufficient 100%
oxygenation during transport, indicating unsufficient on-site management. European Concensus Conference of Hyperbaric Medicine.
ECHM (1996) recommends on-site management:
100% oxygen first aid treatment, fluid administration and directly transport to recompression therapy facility whithin 4 hours after onset.8 In our experiences, Type II DCI is always added by ‘CAGE awareness’ to our staff by monitoring focal-general neurological deficits until recompression therapy is done.
Trendelenburg position is used suggest to prevent CAGE patient become worsening during transport to recompression facility, but it is debatable due to lack of evidence. Bove stated Trendelenburg position is not a choice to decrease the risk of gas embolizing to the brain during transport, instead of a supine position.9
In this case, diagnosing CAGE had an direct impact in management of recompression therapy, but during therapy convulsion state of the patient is redundant to hyperbaric oxygen theraphy. This due to two conditions: inefficient oxygen inhalation or high consentration of oxygen provoke convulsion more severe. Consideration of sedative agent (esp.
Minor tranquilizer) before taking recompression therapy is needed cautiosly. The option of sedative agent is very limited for pre recompression therapy.
Some of sedative agent whithin HBOT may amplify its suppressive effect and the options to choose longer duration of suppressive agent is limited to specially design infusion pump for hyperbaric condition.2,8
Our hospital had an SOP for diving injury incidents management in emergency room. It is cover two most important management: 1. One hundred percent oxygenation is first aid to all
diving injury patients; 2. Fluid administration at least 1.000-1.500 ml normal saline or ringer lactat is given prior recompression therapy to increase effectiveness of therapy.10 Diving activity usually results in some level of dehydration due to immersion diuresis, increased respiratory fluid loss, perspiration and reduced fluid intake, more over in CAGE, plasma leackage occur especially in alveolar capillary.5
We used table 6 US Navy as recompression therapy, but after 20 minutes we consider to stop therapy due to intensify convulsion state. It seems recompression therapy is not effective ins such condition. Anesthesist is preparing ICU for stabilization and overcome convulsion state, but patient decease before reach it. What to monitor in recompression therapy? In CAGE cases, recompression therapy would alleviate unconsciouseness whithin first 10 minutes, reduce cerebral edema and improve general conditions.
The mechanism is HBO reduce bubbles, in 3 ATA bubble volume reduce by about two-thirds. Making possible occlusion of the vessel is released and improve tissue perfusion and oxygenation.
Repeated recompression therapy is needed 12-24 hours later may considerate after follow up right after first recompression therapy.2,11 Monitoring quality of heart pulse: the rhytm, the amplitude and the frequency; convulsion state: reduce cerebral edema is followed by diminish convulsion state;
respiratory: frequency and involvement of volunter respiratory muscle.2,4,12
In conclusion, diagnosing CAGE in hospital equipped with hyperbaric chamber is less complex than hospital not equipped with hyperbaric chamber. Recompression therapy response also confirm the diagnosis. Diagnosing CAGE is important in management and prediction of outcome.
Acknowledgement
dr. H.L. Herman Mahaputra, M.Kes, Director of Mataram City Hospital. Ziadatun Nikmah S, Fourlyta Hutabarat, L. Yuan Apriansah, Budi Hariantoni, Ivan supporting staff of hyperbaric chamber.
References
1. US Navy Diving Manual. Revision 6. SS521- AG-PRO-010/0910-LP-106-0957. April 2008 2. Kindwall, Erick P. Hyperbaric Medicine
Practice. Best Publishing Company. USA.
1994
3. Beckman TJ. A Review of Decompression Sickness and Arterial Gas EmbolismArch Fam Med. 1997:6:491-494
4. Tom S. Neuman (Editor). Physiology and Medicine of Hyperbaric Oxygen Therapy.
Saunders Elsevier Philadelphia. 2008
5. Mathieu D. Handbook on Hyperbaric Medicine. Springer. 2006.
6. Kemper TC, Rienks R, van Ooij PJ, van Hulst RACutis marmorata in decompression illness may be cerebrally mediated: a novel hypothesis on the aetiology of cutis marmorata. Diving Hyperb Med. 2015 Jun;45(2):84-8.
https://www.ncbi.nlm.nih.gov/pubmed/26165 529
7. Wilmshurst PT. Cutis marmorata and cerebral arterial gas embolism.
Diving Hyperb Med. 2015 Dec;45(4):261.
https://www.ncbi.nlm.nih.gov/pubmed/26687 315
8. ECHM Treatment of Decompression Accidents in Recreational Diving. Second European
Consensus Conference on Hyperbaric Medicine 1996, Conseil Général des Bouchesdu-Rhone, Marseilles.
9. Alfred A. Bove, MD, PhD, Professor (Emeritus) of Medicine, Lewis Katz School of Medicine, Temple University. Arterial Gas Embolism
https://www.msdmanuals.com/professional/i njuries-poisoning/injury-during-diving-or- work-in-compressed-air/arterial-gas- embolism
10. Standard Operational Procedures for the Management of Diving Injury. Mataram City Hospital. 2016
11. Branger AB, Lambertsen CJ, Eckman DM.
Cerebral gas embolism absorption during hyperbaric therapy: theory. J Appl Physiol 2001; 90:593-600
12. AL Gill and CNA Bell. Hyperbaric oxygen: its uses, mechanisms of action and outcomes. Q J
Med 2004; 97:385-395.
Doi:10.1093/qjmed/hch074
Experimental Study: Clinical Symptoms of Cerebral Malaria After Exposure to Hyperbaric Oxygen in Mice Infected with P. berghei ANKA
Prawesty Diah Utami1*, Usman Hadi2, Yoes Prijatna Dachlan3, Guritno Suryokusumo4, Luki Enggar Fitri5
1Departement of Parasitology, Faculty of Medicine, Hang Tuah University, Surabaya, Indonesia
2Departement of Internal Medicine, Dr Soetomo – Universitas Airlangga, Surabaya, Indonesia
3Departement of Parasitology, Faculty of Medicine - Universitas Airlangga, Surabaya, Indonesia
4Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
3Departement of Parasitology, Faculty of Medicine - Universitas Brawijaya, Malang, Indonesia
*Corresponding Author:[email protected] Abstract
Cerebral malaria is the most fatal complication and has high mortality. HBO / hyperbaric oxygen becomes adjunctive therapy in various diseases because it has the effect of being an immunoregulator, antiparasitic and improving tissue oxygenation. Administration of 2.4 ATA dose of hyperbaric oxygen; O2 100%; 3 x 30 minutes at 5 minute intervals for 10 days of continuous administration have not been known to have an impact on symptoms of cerebral malaria. This research is an experimental study with a randomized post test only control group design study, using 39 female mice C57BL / 6 infected with 106 P.berghei ANKA / PbA as models of cerebral malaria. Samples were divided randomly in 3 groups : G1 / negative control; G2 / positive control and G3 / group with exposure to HBO. Observations on cerebral malaria symptoms using the scoring of Besnard et al. Descriptive and statistical analysis using the Kruskal Wallis and Mann Whitney tests showed that exposure to HBO in mice infected with PbA significantly reduced cerebral malaria symptoms compared to the positive control group (p <α, α = 0.05).
Keyword : Cerebral Malaria’s symptom, HBO, C57BL/6 mice , P.berghei ANKA.
Background
Malaria is a "Re-emerging Disease" which is an infectious disease that becomes a global problem in the world after experiencing a significant decline in the past (The Ministry of Health Republic of Indonesia, 2015; The Ministry of Health Republic of Indonesia, 2015). Malaria serebral mortality rates reach 18% in children and 25 - 30% in adults. Artemisin as standart treatment of malaria does not guarantee the recovery of patients, because the data show the presence of neurological abnormalities and deaths that reach 15% after adequate therapy. Even 11% of children recovering from cerebral malaria showed severe neurological deficits and more than 25% showed a long-term cognitive (Babikir Haydar El Hadi, 2010; WHO, 2012; (Kayano et al, 2016).
Hyperbaric oxygen / HBO is an act of giving 100 % oxygen systemically in a closed room with a pressure of more than 1 atmosphere / above sea level atmospheric pressure (Gill and Bell, 2004;
Kaide and Khandelwal, 2010). The results of previous studies have shown that HBO 3 ATA for
1 hour has an inhibitory rate inhibition effect, extending the life ability of malaria-infected mice, reducing the excessive inflammatory response by reducing TNF α and IFN γ, decreasing the sequelae of T cells and leukocyte cells in brain tissue significantly (Blanco Y.C., et al, 2008).
Data limitations regarding the effects and mechanism of HBO in malaria infection are the background in this study. Based on these data the researchers wanted to know clinical symptoms of cerebral malaria after exposure to hyperbaric oxygen in mice infected with P.berghei ANKA.
Materials and Methods
The research design used was "Randomized Post Test Only Control Group Design". The experimental unit was 7 - 10 weeks C57BL/6 female mice inoculated with 106 P.berghei ANKA/PbA (Martins et al. 2009; Polimeni & Prato 2014), obtained from the Parasitology laboratory - Faculty Medicine of Universitas Brawijaya and C57BL/6 mice obtained from the Indoanilab Bogor. Ethical approval was obtained from the
ethics committee of the Faculty of Veterinary Medicine - Airlangga University.
Animal Samples
The sample in this study was C57BL / 6 female mice aged 7-10 weeks weighing 14-22 grams. All research groups got standard feed and drinking mineral water that has been sterilized with UV light. Mice were tested for health and weighed to fit the experimental unit inclusion criteria before being used as experimental units. The cage was made of a plastic tube with a woven wire lid, given the base of rice husk and placed in a room that was sufficiently ventilated. One cage measuring 20 X 30 cm was filled with 5 - 6 mice. The mice maintenance room was sterilized 1 day before the study, using ultraviolet light placed in the room and turned on 2 hours every day. The adaptation period is 1 week, if the mice to be sick or aggressive, they are not used in the research and kept in their own cages for treatment. The first stage of the maintenance process (acclimatization stage, inoculation to positive parasitemia level) was carried out in the Brawijaya parasitology laboratory.
The experimental samples will be divided into 3 groups : (G1) Negative control group, mice not inoculated and without HBO, (G2) Group with inoculation of 106 PbA without HBO and (G3) the group with 106 PbA infection with HBO. Total sample on this research was based on the formula of Lameshoe & Lwanga (1997) with α = 0.05; β = 20% and correction factor 30 % were 39 mice.
Determination of mice into each treatment groups were done randomly.
Inoculation of P.berghei ANKA
Blood donor mice of ± 1 ml containing ± 106 parasites were inoculated against donor mice, 0.2 ml each intra-peritoneal. Intraperitoneal injections can be performed on the posterior part of the abdomen. Mice were held on the back, the needle was injected under the knee curve; left or right of the center line. Injection cannot be done on the midline of the abdomen because it can hit the bladder. The tilt angle of the needle is about 45 ° from the body of the mice. Observed the degree of parasitemia starting on day 1 after inoculation up to day 13 after inoculation. Blood was taken the tip of the mice's tail (Suckow, Danneman and Cory, 2001).
Hyperbaric Oxygent Administration
Administration of hyperbaric oxygen is a systemic exposure to high concentrations of oxygen with a pressure of more than one atmosphere. Pressure on the hyperbaric chamber is higher than the pressure in the body (1 ATA).
Pressure in the body tissues (1 ATA) is lower than the pressure when inside the hyperbaric chamber, this condition is in accordance with the conditions when a person dives at a certain depth (Kaide and Khandelwal, 2010). In this study the dose of HBO was 100% oxygen with a pressure of 2.4 ATA 3 times 30 minutes (5 minute interval between exposures) for 10 consecutive days (Susilo et al., 2017). The HBO process is carried out in a hyperbaric laboratory at the Faculty of Medicine, University of Hang Tuah.
Parasitemia Level
The level of parasitemia is an examination technique to detect the number of erythrocytes infected with parasites by using a thick film or thin film blood smears with giemsa staining. Mice that have been inoculated with malaria parasites will be examined for parasitic levels by taking blood through the mice tail and making blood smears with giemsa staining. Observations were made through a binocular microscope with 1000x magnification and counting the number of infected erythrocytes in 1000 observed erythrocytes multiplied by 100 (Adetutu et al., 2016).
Observation of the level of parasitemia was carried out from day 1 after inoculation to day 13 after inoculation.
Clinical Symptoms of Cerebral Malaria
The effect of HBO administration on mice was assessed based on the clinical symptoms of cerebral malaria that appeared. Observations were carried out every day in all groups infected with PbA starting from day 1 and day 11 after inoculation. Clinical symptom assessment is done by a score from Besnard et al. (2015). Observation of clinical signs that appear is assessed by scoring as follows :(1) no clinical signs; (2) ruffle fur and / or abnormal posture; (3) lethargy; (4) response to decreased stimulation and / or ataxia (motor coordination disorders) and / or respiratory disorders / hyperventilation; (5) prostation position / lengthen the body such as prostrating and / or
paralysis and / or convulsions. If the clinical score is more than or equal to 4, the experimental animal is declared to have cerebral malaria (Besnard et al., 2015).
Results and Discussion
Serial examination of cerebral malaria’s symptoms starts from day 3 to day 13 after inoculation, using scoring from Besnard et al (Besnard et al., 2015). Positive control group (G2), 1 sample showed symptoms of cerebral malaria (score 4) on day 11 after inoculation, 12 samples showed symptoms on day 12 after inoculation. In the HBO (G3) treatment group, 3 samples appeared with cerebral malaria symptoms (4th score) on the 12th day after inoculation and 4 samples showed cerebral malaria symptoms appearing on day 13 after PbA inoculation. The results of the examination of cerebral malaria symptoms in all the study groups on day 13 after inoculation can be seen in the table below :
Table 1. Score of Cerebral Malaria Symptoms on Day 13
SCORING CM
GROUPS
TOTAL
G1 G2 G3
1 33.33 0.00 0.00 20.51
2 0.00 0.00 0.00 12.82
3 0.00 0.00 15.38 15.38
4 0.00 30.77 17.95 48.72
5 0.00 2.56 0.00 2.56
Total Samples Had Score >
Or = 4
0 33.33 17.95 51.28
G1 : negative control group (no PbA infection and without HBO).
G2 : Positive control group (PbA infection without HBO).
G3 : Group with PbA infection and HBO
Based on the data in the table above it can be concluded that total samples had cerebral malaria’s symptoms were 51.28 %; G2 (33.33 %) had the highest score of cerebral malaria”symptoms than G1 (0 %) and G3 (10.26 %). All mice in the G2 had symptoms of cerebral malaria which 13 from 39 samples (33.33 %), G2 had 7 from 39 samples (17.95 %) had a score 4 and G1 had no sample with cerebral malaria’s symptoms (0 %). Statistical analysis using non parametrik analysis ( Kruskal Wallis) showed p = 0.0001, p < α = 0.05. Post hoc analysis / Mann whitney analysis also showed significant differences between the 2 groups
studied (G1 with G2 and G3; G2 with G3) with p values <α = 0.05.
Based on the results of descriptive analysis and statistics it can be concluded that the administration of HBO 2.4 ATA with 100% O2; 3 x 30 minutes for 10 consecutive days can affect the clinical symptoms of cerebral malaria by significantly reducing the appearance of symptoms of cerebral malaria
Cerebral malaria is a reversible encephalopathy caused by the Plasmodium parasite, especially P.falciparum. The pathophysiology mechanism of cerebral malaria is still unclear, due to the limited data in human samples. Examination of brain tissue in humans is very limited due to safety factors, so brain examination is only done through an autopsy examination. Because of these limitations, the study of cerebral malaria was mostly carried out in C57BL/6 or CBA mice infected PbA. Although it produces various important information but there are differences in pathogenesis in humans and mice so that not all findings in mice can be extrapolated directly to humans. The first factor that is thought to be the cause of cerebral malaria is the sequestration process of infected erythrocytes in microvascular endothelial cells of brain tissue, causing damage to capillary blood vessel walls, inhibiting blood flow to capillary blood vessels, causing failure of brain function (Rao et al. 2010;
Kimoloi & Rashid 2015). The second factor that causes is endothelial damage due to apoptosis and CD 8 cell activity 8. Endothelial damage is triggered by pRBC sequestration in the endothelium which stimulates the occurrence of apoptosis and cytotoxicity processes of CD 8 cells 8 (Pino et al., 2005; (El-Assaad Fatima, Combes V., Grau, 2014; Canavese and Roberta, 2014). The third factor associated with cerebral malaria is the occurrence of an inflammatory process excessive.
Various cytokines and chemokines have two opposite effects, one side is protective but on the other hand it can be detrimental. Parasitic antigens that come out when pRBC ruptures can trigger the release of various pro and anti-inflammatory cytokines. The balance between the role of pro and anti-inflammatory cytokines plays a role in parasitic control (Shan et al., 2012; Storm and Craig, 2014; Kimoloi and Rashid, 2015).