Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports

Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports Harri Hemilä, MD, PhD 1), Angelique M.E. de Man, MD, PhD 2) 1. Department of Public Health, University of Helsinki, POB 41, Helsinki, Finland 2. Department of Intensive Care Medicine, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands [email protected] https://orcid.org/0000-0002-4710-307X [email protected] https://orcid.org/0000-0001-8738-8295 SUPPLEMENT 1 2024-2-21 This is supplement to a paper submitted to BMC Pulmonary Medicine https://bmcpulmmed.biomedcentral.com Contents Page Search for case reports on scurvy and pulmonary hypertension 2 Fig. S1: Heart rate, respiratory rate, and blood pressure by the age of the patient 3 Fig. S2: Reported improvement in cardiac outcomes over two weeks after the start of vitamin C 4 Fig. S3: Association of scurvy with TAPSE and the diameter of inferior vena cava 5 Fig. S4: Effect of vitamin C on cardiac outcomes in pulmonary hypertension patients 6 Abbreviations used in the description of the 32 cases 7 A case report published after the completion of the systematic review 8 Description of the 32 included case reports 9 1 Search for case reports on scurvy and pulmonary hypertension. PubMed On 2023-7-9, we carried out a search using the following search terms: ("pulmonary hypertens*" or "pulmonary arterial hypertension") and ("vitamin c" or ascorb*) This gave 46 records Scopus On 2023-7-9. we carried out the following search: ( TITLE-ABS-KEY ( "pulmonary hypertens*" OR "pulmonary arterial hypertension" OR "right heart failure" ) AND TITLE-ABS-KEY ( "vitamin c" OR ascorb* ) ) This gave 178 records Web of Science (Clarivate) On 2023-5-13, we looked at the citations for the major identified case reports and carried out a search for citing publications. The reports used in this search were the following: Dean T (2019) [82], Duvall MG (2013) [83], Frank BS (2019) [85], Gayen SK (2020) [86], Ghulam Ali S (2018) [87], Ichiyanagi S (2019) [89], Kupari M (2012) [90], Mehta CL (1996) [92], Mertens MT (2011) [93], Penn EH (2019) [96]. This search gave 94 records. We also read all the reference lists of the identified case reports. Together, these approached gave us 32 case reports about scurvy and pulmonary hypertension. 2 Fig. S1. Heart rate, respiratory rate, and blood pressure by the age of the patient. Data were not available for all cases. For the age range <18 years, the blue continuous line indicates the upper limit, and the red dash line indicates the lower limit for the the estimated 90% coverage of normal population [106]. See extraction of data in Supplements 1 and 2. 3 Fig. S2. Reported improvement in cardiac outcomes over two weeks after the start of vitamin C. In the ordinary hospital context, there is no regular daily follow-up by echocardiography or other examinations. Instead, repeat examinations are usually carried out after fixed time periods. Therefore, this recovery curve is biased towards delayed documented recovery. Nevertheless, this analysis indicates that about half of the cases demonstrated cardiac improvement within 2 weeks. The cardiac outcomes used in this figure are heterogeneous, including measures from echocardiography and catheterization, see Supplements 1 and 2. Time point 0 indicates the start of vitamin C administration. 4 Fig. S3. Association of scurvy with TAPSE and the diameter of inferior vena cava. A 25-year-old female in the USA [91]. Four months before admission to hospital, TAPSE was 23 mm, and when scurvy was diagnosed, it was 9.5 mm (filled circles on left). There are no TAPSE data after vitamin C was started. Inferior vena cava was 23 mm when scurvy was diagnosed, and 14 mm after vitamin C was administered (open triangles on right). The scale is different on the lefthand side. Period of scurvy is around day 0, which is the day of admission to hospital. The day when vitamin C was started was not published. 5 Fig. S4. Effect of vitamin C on cardiac outcomes in pulmonary hypertension patients. A. a 40-year-old female in Finland [90]. The RV + RV area with filled circles on the left-hand side, and diameter of inferior vena cava with open triangles on the right-hand side. B. a 6-year-old male in the USA [98]. The RV systolic to diastolic duration ratio with filled circles on the left-hand side, and RV area change with open triangles on the right-hand side. 6 Abbreviations used in this Supplement ALP, alkaline phosphatase ALT, alanine transferase ASD, autism spectrum disorder AST, aspartate transferase BNP, brain natriuretic peptide BP, blood pressure CT, computed tomography CTA, CT angiography CXR, chest X-ray DLCO, diffusing capacity for carbon monoxide DVT, deep vein thrombosis ECG, electrocardiogram ECHO, transthoracic echocardiogram ESR, erythrocyte sedimentation rate FEV1, forced expiratory volume in 1 second FVC, forced vital capacity Hb, hemoglobin HD, hospital day HR, heart rate ICU, intensive care unit INR, internalized normalized ratio (measure of blood clotting and liver function) LV, left ventricle/ventricular LVEF, left ventricular ejection fraction mPAP, pulmonary artery mean pressure (can be estimated from sPAP: mPAP = 0.61×sPAP + 10) PAH, pulmonary artery hypertension PAP, pulmonary artery pressure; mPAP, mean PAP, sPAP, systolic PAP sPAP, pulmonary artery systolic pressure (can be estimated from TRPG: sPAP = TRPG + 10) PH, pulmonary hypertension RA, right atrium/atrial RBBB, right bundle branch block RHF, right heart failure RV, right ventricle/ventricular SpO2, oxygen saturation level SR, sinus rhythm TAPSE, tricuspid annular plane systolic excursion index TR, tricuspid regurgitation TRV, TR velocity (m/s) TRPG, tricuspid regurgitation pressure gradient (= 4×TRV2; used to estimate sPAP) 7 A case report published after the completion of the systematic review After we received the reviewer reports, we noted a new report (2024) on two cases of PH induced by scurvy [1]. The two cases are consistent with the set we included in our analysis, but we did not append them to our analysis. This is a brief summary of the cases. Case 1 was a 2-year-old boy presented to hospital with vomiting, diarrhea, and fever. He had hypotension and was transferred to the pediatric intensive care unit where he suddenly collapsed and had confirmed cardiac arrest. The mPAP was 49 mmHg, based on peak TRV of 4.1 m/s. Three days after referral, the right cardiac catheterization showed mPAP 20 mmHg. Vitamin C level was undetectable. The boy was administered 0.3 g/day vitamin C. After he was discharged from the hospital, his symptoms gradually improved and returned to his usual state of health within 2 weeks. At the one-year follow-up, he has been well with normal PAP. Prior to the episode, the boy had restrictive eating patterns. His dietary preference were rice, pork, eggs, and milk, with very few vegetables and fruits. Case 2 was a 6-year-old boy with ASD. He had progressive dyspnea and low-grade fever for 1 month and refused to walk due to his swollen, painful left knee. Chest x-ray revealed mild cardiomegaly with prominent pulmonary artery trunk. Echocardiography showed enlargement of RA, RV, and main pulmonary artery and mPAP was 36 mmHg (peak TRV of 3.4 m/s). Right cardiac catheterization found mPAP 50 mmHg. His dietary intake consisted mainly of rice and egg with avoidance of milk, vegetables, and fruit. Vitamin C level was undetectable. With a dose of 0.3 g/day vitamin C, his symptoms improved gradually in 2 weeks, and he could walk in 1 month. His 2-year echocardiographic follow-up was normal without signs of PH. 1. Satawiriya M, Khongphatthanayothin A, Limsuwan A. Reversible severe pulmonary hypertension related to scurvy in children. BMC Cardiovasc Disord. 2024;24(1):24. https://doi.org/10.1186/s12872-023-03629-6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765653 8 Description of the 32 included case reports Abbas (2016) [76] https://pubmed.ncbi.nlm.nih.gov/27682441 Patient 50 y woman, previously healthy. Never smoked, drank alcohol, or used recreational drugs. No current medications. Duration of the symptoms before hospital 3 months Signs and symptoms Progressively worsening shortness of breath associated with extreme fatigue, anorexia, about 5 kg weight loss, yellowing of eyes, heavy menstrual bleeding, and a lower extremity rash. Main findings Neck veins were distended to her earlobes when sitting. Massive hepatomegaly. A nonconfluent, nonblanching petechial rash on anterior legs, and a large ecchymosis on her thighs and buttocks. HR 92/min, BP 91/56 mmHg, respiratory rate 20/min. SpO2 85% on room air. ECG showed SR with low voltage in the anterioinferior leads. CT showed periportal edema with hepato-splenomegaly, enlarged and inferior vena cava, portal vein, and splenic vein. ECHO showed enlarged RA and RV, septal flattening, right ventricular moderate hypokinesis, and mild-to-moderate TR without systolic reversal in the hepatic vein. No evidence of LV dysfunction. Hb 34 g/L, MCV 90 fL, Fe 90 ug/L, ferritin 147 ng/mL AST 726 U/L, ALT 670 U/L, ALP 154 U/L, INR 2.2 BNP 347 pg/mL (normal <100). Viral hepatitis: negative. B1 and folate normal Vitamin C plasma level 1 mg/L ( 5.7 µM) Drugs in hospital None Other vitamins and minerals Diet before the event Diet at home was strictly limited to cereal, eggs, and milk. Vitamin C treatment Vitamin C dose and route not reported. Effect of vitamin C Symptoms improved rapidly and remarkably. Heavy menstrual bleeding improved and liver enzymes normalized. At 4 weeks, ECHO was completely normalized with no evidence of RV dysfunction and normal PAP. NOTES To ask for further details of the case, we contacted Farrukh Abbas by email on 2023-2-8 and 2023-2-23 but did not get a response. 9 Benhamed (2019) [80] https://doi.org/10.3166/afmu-2019-0169 Patient 40 y male. Rheumatoid purpura in childhood. Duration of the symptoms before hospital 10 days. Signs and symptoms Worsening exertional dyspnea. Asthenia, epistaxis. Main findings HR 130/min, BP 150/81 mmHg. SpO2 of 86% on room air. No signs of heart failure. ECG SR, no abnormalities. Angiography excluded pulmonary embolism. ECHO revealed RV dilatation, paradoxical septum. sPAP 100 mmHg. Laboratory results: Arterial blood gass pH 7.55, PaCO2 21 mmHg, PaO2 58 mmHg, lactate 3.7 mmol/l D-dimer 643 µg/L Vitamin C level undetectable (<5 µM). In addition, vitamin K deficiency. Drugs in hospital Diuretic therapy (not specified) “Après traitement diurétique” Other vitamins and minerals Diet before the event Food allergies. Exclusively dairy products for several years. Vitamin C treatment Vitamin C dose and route not reported. Authors write “From a therapeutic point of view, daily administration of vitamin C (1 g/d), divided into several doses daily for 15 days, remains the historical reference” [our translation], but they do not state explicitly that 1 g/day was used for their patient. Effect of vitamin C Day 2 sPAPs 70 mmHg and amelioration of symptoms. Day 7 ECHO sPAP 28 mmHg. “After diuretic treatment and vitamin C supplementation, the patient presented a marked improvement in symptoms, including a partial regression of purpuric lesions and PAH (PAPs measured at 70 mmHg at 48 hours). On the seventh day management, ultrasound control in cardiology measured PAPs at 28 mmHg” [our translation]. Time series In their paper, authors reported [free translation]: [baseline sPAP during scurvy] “systolic pulmonary arterial pressure (sPAP) measured at 100 mmHg… a marked improvement in symptoms, including partial regression of purpuric lesions and PAH (sPAP was 70 mmHg at 48 hours). On the seventh day of treatment, a repeat cardiologic ultrasound measured sPAP of 28 mmHg.” 16 These figures are shown in our graph. NOTES To ask for further details of the case, we contacted Dr. Benhamed by email on 2023-5-13 and 2023-5-23 but did not get a response. 17 Conte (2021) [81] Lauren Ann Weber https://pubmed.ncbi.nlm.nih.gov/33960312 Patient 48 y female. Generalized anxiety and interstitial cystitis. Recently liver injury secondary to polypharmacy. Duration of the symptoms before hospital 2 weeks Signs and symptoms Rest and exertional dyspnea. Lower extremity edema, early satiety, increased abdominal girth. Main findings Anasarca. New systolic and diastolic cardiac murmurs. NT-proBNP elevated, no data Cardiac troponins normal, no data CT angiography and invasive coronary angiography excluded pulmonary embolism and coronary artery disease. ECHO revealed normal LV systolic function, biatrial enlargement, moderate to severe mitral regurgitation, moderate aortic insufficiency, severe TR, decreased RV function, and moderate to severe PH. The estimated sPAP was 60 mmHg. Microbubble study was negative for intracardiac shunting. Right heart catheterization demonstrated elevated leftand right-sided pressures, with an RA pressure of 20 mmHg, mPAP 35 mmHg, mean pulmonary wedge pressure 16 mmHg, and cardiac index of 2.1 L/min/m2 using the Fick equation. PVR not reported Vitamins B1, B6, B12, D, E, folate, Se, Zn normal (Table 1 shows data) Vitamin C level undetectable. Drugs in hospital Diuretic therapy (not specified) led to improvement Other vitamins and minerals Diet before the event Had been avoiding foods containing vitamin C to decrease her interstitial cystitis symptoms as per internet guidance. Vitamin C treatment “vitamin C repletion” but dose and route not reported. Effect of vitamin C 1 month later, hypervolemia and end organ dysfunction. Repeat right heart catheterization demonstrated a cardiac index of 1.5 L/min/m2 using the Fick equation. Vitamin C levels were at the lower normal limit. The patient was started on milrinone and referred for valve surgery. She underwent aortic and mitral valve replacement and tricuspid valve annuloplasty while continuing vitamin C. NOTES We were able to contact Lauren Ann Weber in 2023-2-23, with the following response: “I apologize I don’t have the information any longer.” 18 Dean (2018) [82] Paul Kim https://pubmed.ncbi.nlm.nih.gov/30351242 Patient 6 y boy. Duration of the symptoms before hospital 3 months Signs and symptoms Bilateral lower extremity pain and refusal to bear weight. Before proceeding with planned bone biopsy, the boy became acutely tachycardic, hypotensive, and pulseless. Returned to spontaneous circulation and a dopamine infusion was started, leading to stable blood pressures. Main findings BNP 850 pg/mL (normal <100). Post-arrest ECHO, performed while on a dopamine infusion and shortly following epinephrine and phenylephrine boluses, demonstrated tachycardia 138 bpm with hyperdynamic LV systolic function (shortening fraction = 61%). Insufficient TR for estimation of RV pressures, but mild septal flattening was suggested. A later, retrospective review of the above ECHO demonstrated an abnormal RV/LV diameter ratio of 1.7 [>1 has been associated with increased adverse events in pediatric PH]. LV eccentricity index (LVEI) was abnormal at 1.7 [LVEI > 1 in adult PH suggests impaired RV function]. The pulmonary artery acceleration time (PAAT) in the postarrest ECHO showed an abnormal value of 90 ms (normal ≥ 100 ms). Hospital day 3 BNP 2716 pg/mL, and developed poor urine output and peripheral edema. Hospital day 5 ECHO showed significant RV dysfunction with both RA and RV dilation and prominent septal bowing. There was increased TR, with TR jet based pressure gradient 68 mmHg (excluding RA pressure). Concern for PH prompted a retrospective review of the original post-arrest ECHO and a more detailed assessment of the RV function. The RV/LV diameter ratio had increased to 2.8, while the LVEI had increased to 2.85. The PAAT was inadequately assessed on HD5, in part because the Doppler flow pattern in the pulmonary artery was low at <50 cm/s (consistent with low RV output). Hospital day 8 CT arteriogram of the chest, abdomen, and pelvis did not find evidence of pulmonary embolus or vasculitis. Hospital day 9 Catheterization confirmed mild PH. PVR index 3.5 Wood units × m2 (Table 1) We assume body surface are 0.85 m2 which gives PVR = 4.1 Wood units. 19 Wedge pressure 4 mmHg. mPAP 12-13 on iNO and milrinone. Hospital day 10, Vitamin C level undetectable, <5 µM. Vitamin A level undetectable. Vitamins B1, B3, B6, B12, D, E, Zn normal (Table 2 shows data) Drugs in hospital Dopamine after cardiac arrest Epinephrine Phenylephrine iNO on HD5 and symptoms and ECHO improved Milrinone on HD5 and symptoms and ECHO improved Sildenafil on HD10, and subsequently was weaned off iNO and milrinone. Other vitamins and minerals Vitamin A 10000 IU/day. Diet before the event Diet lacked fruit, vegetables, vitamins, or fortified foods, resulting in multiple vitamin deficiencies. Vitamin C treatment HD10: Vitamin C 0.3 g/d intravenously. Effect of vitamin C By hospital day 12, BNP had normalized and ECHO parameters had nearly normalized (LV/RV diameter ratio of 0.9, LVEI 1.11–1.18, PAAT 140 ms, TR jet based pressure gradient 19 mmHg (excluding RA pressure), mild septal flattening but qualitatively normal RV function). At 6 months, ECHO demonstrated no evidence of PH, and he was weaned off sildenafil. At 12 months, he remained asymptomatic with a reassuring ECHO. NOTES To ask for further details of the case, we contacted Paul Kim by email on 2023-2-8 and 2023-2-23 but did not get a response. 20 Duvall (2013) [83] https://pubmed.ncbi.nlm.nih.gov/24190688 Patient 9 y boy with ASD. Duration of the symptoms before hospital 4 months Signs and symptoms Developed a limp. Neurologic and orthopedic evaluations did not reveal an etiology. Symptoms worsened despite physical therapy. Finally, entirely unable to ambulate, and developed a dry cough and labored breathing. Main findings HR 135/min, BP 79/66 mmHg, respiratory rate of 26/min. SpO2 of 96% on room air. Was given normal saline, without improvement in tachycardia, persistent tachycardia continued 140-170 bpm, respiratory rate up to 56/min, evolving hypoxia required supplemental oxygen by facemask. Early laboratory tests BNP 2019 pg/mL (normal <100) CRP 13 mg/L ESR 23 mm/h (normal <20). CXR showed diffuse, nodular, ill defined airspace opacities throughout the right lung greater than left lung (consistent with cardiogenic pulmonary edema versus pneumonia) and small right pleural effusion and an enlarged main pulmonary artery. ECG showed sinus tachycardia with a left axis deviation, and right heart strain pattern with incomplete RBBB, and nonspecific ST and T-wave changes. CT angiogram showed normal pulmonary veins, a dilated main pulmonary artery (3.2 cm), and no filling defects, excluding pulmonary embolism. Lower limb Doppler ultrasound excluded DVT. ECHO showed a severely dilated RV with mild to moderately depressed systolic function and a dilated RA and pulmonary artery. RV pressures determined by TRV sPAP 65 to 70 mmHg plus the right atrial v-wave, mPAP 45 mmHg, and end-diastolic pressure of 30 mmHg plus the right atrial pressure (not wave) determined from the pulmonary regurgitant velocities. Serial ECHOs on HD 2, 3, and 4 showed persistent severe elevation of RV pressure as well as severely dilated RV with moderate dysfunction. Vitamin B1 55 nmol/L (normal 70-180) Vitamin B6 3.5 ng/mL (5-30) Vitamin B12 <150 pg/mL (190-778) Vitamin D 8.2 ng/mL (30-80) 21 Vitamin C level undetectable, <5 µM. Drugs in hospital No PH drugs Antibiotics for suspected pneumonia. Other vitamins and minerals Vitamins B1, B12 and D were administered with a multivitamin preparation. After 3 weeks, a multivitamin preparation, and calcium and vitamin D were continued. Diet before the event For the past 3 y, the boy had eaten chicken nuggets, crackers, cookies, and water. Refused milk, juice, vegetables, and fruits and was not on vitamin supplementation. Vitamin C treatment Starting on HD 6, vitamin C was administered intravenously, but dose was not described. Effect of vitamin C By HD 11 (5 days vitamin C), respiratory rate had decreased to the normal range. By HD 15 (9 days vitamin C), a repeat ECHO showed RV pressure less than half systemic pressure by septal position and resolution of RV dilation and normal systolic function. At the time of discharge, at 3 weeks, he was able to ambulate with assistance without pain. Over 18 months, vitamin levels remained normal on vitamin supplements, and repeat ECHO showed normal RV pressures and function. NOTES To ask for further details of the case, we contacted Melody Duvall by email on 2023-2-8 and 2023-2-23 and 2023-3-4 but did not get a response. 22 Ferreira (2020) [84] https://pubmed.ncbi.nlm.nih.gov/32133311 Patient 51 y male. Paranoid personality disorder, low socioeconomic status. Duration of the symptoms before hospital 1 month Signs and symptoms Dyspnea on minimal exertion, lower limb edema and painful bruises on the lower limbs. Main findings Lower limbs presented perifollicular hemorrhage, bilateral pitting edema and painful nodules and bruises. Tachycardia, respiratory rate 20/min, SpO2 of 98%. ECG showed ST-segment elevation in leads DII, DIII and AVF associated with inverted T waves in leads V1-V4. Chest CT and perfusion/ventilation scan excluded pulmonary embolism. Lower limb Doppler ultrasound excluded DVT. ECHO showed enlarged RA and RV and RV systolic dysfunction: the difference between the RV area during diastolic and systolic stages (14.5 – 17.5 cm2) was 15% (normal 30%). Estimated sPAP 61 mmHg with mild TR. Cardiac markers normal, but levels not reported. Hb 51 g/l Fe 23 µg/dL (normal 59-158). Folic acid 2.07 ng/mL (>5) Vitamin B12 118 pg/mL (210-980) Vitamin C level 0.5 mg/L (2.8 µM). Drugs in hospital None Other vitamins and minerals Diet before the event Patient had been thinking that someone in his house was poisoning his meals, and therefore restricted his intake of food, including fruit and vegetables. Vitamin C treatment Vitamin C 1 g/day intravenously was initiated in the hospital. After discharge, oral vitamin C was continued. Effect of vitamin C At 16 months, repeat ECHO did not show PH, and revealed normal RV function. NOTES 23 Frank (2019) [85] https://pubmed.ncbi.nlm.nih.gov/30738657 Patient 17 y male, who spent hours indoors playing video games. Developmentally normal, thriving adolescent. Duration of the symptoms before hospital 2 weeks Signs and symptoms Leg pain, bruising without trauma, and chest pain. Main findings Symmetric pedal edema, bilateral lower extremity tender ecchymosis, petechiae, corkscrew hairs. Cardiac exam found loud P2. No unusual findings in X-ray of lower extremity and chest, MRI of the lower extremities, pelvis, and abdomen, CT with angiography of the chest, bilateral lower extremity ultrasound, and ECG. ECHO showed a structurally normal heart with PH with TRV 4.2 m/s. NT-proBNP 140 pg/ml BNP <15 ng/L Hb 111 g/L MCV 76 fL Fe 25 ug/dL Ferritin 76 ng/mL CRP 57 mg/L ESR 19 mm/h Vitamin D 17.8 ng/mL Vitamin C level undetectable. Drugs in hospital None Other vitamins and minerals Vitamin D Fe Diet before the event Diet devoid of fruits and vegetables. Vitamin C treatment Vitamin C supplement dose was not reported; term supplement suggests oral administration. Effect of vitamin C After 2 days, symptoms improved and he was discharged home. After 1 month, TRV 3.1 m/s and the symptoms had resolved. After 6 months, TRV 2.4 m/s, leg hairs had straightened, and was clinically well. Time series “An echocardiogram … (tricuspid regurgitation [TR] velocity of 4.2 m/s). ... treated with … ascorbic acid … One month later, his TR peak velocity was 3.1 m/s and the symptoms had resolved. 24 After 6 months, his TR peak velocity had normalized (2.4 m/s)” These figures are shown in our graph. NOTES We were able to contact Benjamin Frank, who responded 2023-2-9 to our question about vitamin C dose and route as follows: “vitamin C supplement was definitely given orally, I don't remember the dose...” Same day further about dose and echo data: “It would depend on finding the records to get the dose. The patient presented 5 or 6 years ago so I don’t think memory will hold. We did not do a heart cath in either case so the diagnosis of PAH was empiric based on the data we had and what is known about vit c effect on the lung.” 25 Ichiyanagi (2019) [89] https://pubmed.ncbi.nlm.nih.gov/31567273 Patient 3 y with ASD. Duration of the symptoms before hospital No data about duration Signs and symptoms General fatigue, shortness of breath. Acute heart failure, decreased deep tendon reflexes, unstable gait. Main findings CXR showed cardiac dilation and an enlarged main pulmonary artery. ECHO showed a dilated RV with a RV/LV basal diameter ratio of 1.3, TRV 4.1 m/s, and interventricular septal flattening. Pro-BNP 14,513 pg/mL (normal <125). Vitamin B1 20 ng/mL (21.3–81.9). Vitamin B1 was initiated. Hospital day 8 HR 135/min, BP 105/93 mmHg, respiratory rate 36/min, SpO2 100% on room air Cardiac catheterization was scheduled under general anesthesia. Circulatory collapse occurred in a few minutes, and the procedure was cancelled, and transferred to pediatric ICU. Hospital day 19 Cardiac catheterization: mPAP 77 mmHg (PAP range 98/64 mmHg). PVR index 22.62 Wood unit × m2. Below: BSA 0.55 m2 Thus, PVR = 41.1 Woods units Cardiac index 2.98 L/min/m2 Tadalafil was initiated. Hospital day 21 The patient developed gingival bleeding and was found to have bilateral humeral fractures on X-ray. Vitamin C level undetectable. Drugs in hospital Tadalafil Other vitamins and minerals Vitamin B1 Diet before the event For 3 months, only chicken and rice, without fruit and vegetables. Vitamin C treatment Vitamin C intravenously 0.5 g/day, see NOTES. Effect of vitamin C After 1 day, the hemorrhagic diathesis improved and ECHO showed improvement of the RV dilation and TR (RV/LV basal diameter ratio, 1.0; TRV 2.4 m/s). “After initiating vitamin C therapy, the findings of PH on [ECHO] improved the following day and the clinical manifestations (ie, gingival bleeding, general fatigue, shortness of breath) improved within 2 weeks” 32 After 6 weeks, repeat ECHO showed sustained improvement of PH on vitamin C therapy, without tadalafil. Cardiac catheterization: mPAP 19 mmHg (PAP range 26/12 mmHg). PVR 2.32 Wood units. Cardiac index 4.32 L/min/m2 Time series Dr. Ichiyanagi kindly provided us with the data for our time series graph, see below. NOTES We were able to contact Shogo Ichiyanagi, who responded 2023-2-9 to our question about vitamin C dose and route as follows: What was your dose of vitamin C and was that orally or iv? “The dose of vitamin C was as follow; week 1: 250mg twice a day/ i.v. week 2: 250mg once a day/ i.v. week 3: 125mg once a day/ i.v. week 4-6: 40mg twice a day/ p.o. week 7-: 40mg twice a day/ p.o.” “We still have the echo data. The peak velocity of TR after 6 week was 2.0 m/s.” Shogo Ichiyanagi sent more data on 2023-2-20. 33 pre post TR velocity 3.7m/sec 2.1m/sec TRPG 56mmHg 17mmHg TAPSE 13.0mm 17.5mm e'/a'/s' 8.3/10.4/10.7 16.1/10.6/12.3 41.4/53.2 54.6/55.1 ventricular septum flat round RV basal diameter/ LV basal diameter >1.0 <1.0 eccentrisity index not appricable not appricable RV-FAC 21% 49% RVdiameter not appricable not appricable RV-Tei index 0.53 0.03 RV sys to dia duration ratio 1.8 1.1 acceleration time 40 130 PR velocity not appricable not appricable PA diameter 16.3 16.1 RA diameter 6 6.1 TMF e/a See further data on the next page. Ichiyanagi sent further data about ECHO and catheterization on 2023-2-24. 34 event (pre echo) 1st. cardiac catheterizatio n (PH crisis) 2nd. cardiac catheterizatio n (Before) Diagnosed possible scurvy. Vit.C was initiated date 12/22 12/24 12/26 12/27 12/28 1/1 1/2 1/4 1/5 1/8 1/10 1/11 hospital day 1 3 5 6 7 11 12 14 15 18 20 21 TR velocity (m/s) 2,6 3,4 4,1 3,7 4,9 4,7 4,4 3,7 4,9 3,8 4,0 TRPG (mmHg) 27 46 67 56 97 87 77 56 97 58 64 TAPSE (mm) 13.0mm e'/a'/s' 8.3/10.4/10.7 TMF e/a 41.4/53.2 ventricular septum flat RV basal diameter/ LV basal diameter >1.0 eccentrisity index not appricable RV-FAC 21 % RVdiameter not appricable RV-Tei index 0,53 RV sys to dia duration ratio 1,8 acceleration time 40 PR velocity not appricable PA diameter 16,3 RA diameter 6 BSA (m2)0,55 Wedge pressure (FiO2 1.0) (mmHg) 9,5 Wedge pressure (FiO2 1.0 + NO20ppm) (mmHg) 11 event (post echo) Approximatel y 6 weeks after the start of vit C administratio n 3rd. cardiac catheterizatio n (After) ent date 1/12 1/13 1/15 1/24 1/31 2/8 2/16 2/22 2/26 2/27 3/2 hospital day 22 23 25 34 41 49 57 63 67 68 71 TR velocity (m/s) 2,4 2,1 2,4 2,3 2,6 2,4 2,0 TRPG (mmHg) 22 18 24 21 27 23 17 TAPSE (mm) 16,1 19,8 17,3 17,3 17.5mm e'/a'/s' 14.0/14.5/15.3 13.0/12.5/15.6 10.7/11.2/15.0 12.2/12.7/16.1 10.9/10.1/13.1 16.1/10.6/12.3 TMF e/a 54.6/55.1 ventricular septum round RV basal diameter/ LV basal diameter 1,0 <1.0 eccentrisity index not appricable RV-FAC 49 % RVdiameter not appricable RV-Tei index 0,03 RV sys to dia duration ratio 1,1 acceleration time 130 PR velocity not appricable PA diameter 16,1 RA diameter 6,1 BSA (m2)0,56 Wedge pressure (FiO2 1.0) (mmHg) 9 Wedge pressure (FiO2 1.0 + NO20ppm) (mmHg) 11 Kupari (2012) [90] https://pubmed.ncbi.nlm.nih.gov/22796843 Patient 40 y woman with mild asthma and food allergies. Duration of the symptoms before hospital 18 months Signs and symptoms Tender red-bluish nodules, ecchymoses, and palpable purpura on legs 18 months earlier. Acute issue was anemia, increasing breathlessness, and subcutaneous bleeding. Main findings There were large subcutaneous hematomas on her legs but she was in no acute distress. HR 105 bpm, BP 115/75 mmHg, SpO2 of 100% on ambient air. ECG showed flattening of the T waves in the right precordial leads. CXR normal. Oral Fe administration was started. Because of a vague suspicion of vasculitis, treatment with oral prednisone was initiated. Within a few days, the patient became increasingly dyspneic and SpO2 dropped to 77-80% on ambient air. Oxygen was administered. ECHO showed a dilated and poorly contracting RV, TRV 3.5 m/s, an eccentrically deformed LV, pericardial effusion, and flow from right to left atrium through open foramen ovale. Dilated right side of the heart and severely flattened LV. CTA revealed dilatation of the pulmonary artery but no pulmonary embolism. A ventilation-perfusion scan excluded pulmonary embolism. Right-sided heart catheterization, with the patient breathing room air, revealed severe precapillary PH, RV failure, and a large right-to-left shunt. mPAP 48 mmHg (PAP range 74/36 mmHg). PVR 30 Wood units (2400 dyn/s/cm5). Wedge pressure 3 mmHg. Echo: RV+RA 52 cm2 Vena cava inferior max diameter 27 mm LV eccentricity index 2.5 TAPSE 7 mm Hb 74 g/L. Fe 5.4 µM (normal 9-34). 35 Transferrin saturation 10% (17%-52%). Transferrin receptor 7.0 mg/L (1.9-4.4). Vitamin C level undetectable, <10 µM. Drugs in hospital Prednisolon, rapidly tapering doses after discharge Epoprostenol Sildenafil was initiated, but discontinued 3 weeks later. Other vitamins and minerals Fe, discharged with Fe administration Diet before the event For several years, diet had been deficient of fruit and vegetables, because of proven and presumed food allergies. Vitamin C treatment Vitamin C 1 g/day orally. Sildenafil was discontinued 3 weeks later. Therefore, we classify the treatment as vitamin C alone. Effect of vitamin C In 2 days, she experienced relief of dyspnea and normalization of SpO2. After 1 week, control ECHO showed no signs of PH. After 8 weeks (with 5 weeks off sildenafil), she reported normal exercise capacity and had normal Hb 140 g(L Findings at catheterization and ECHO showed that the PAP, flow, and resistance were completely normal, as was right-sided heart function. Echo 1 week: RV+RA 38 cm2 LV eccentricity index 1.0 Vena cava inferior max diameter 18 mm TAPSE 20 mm Echo 8 weeks: RV+RA 28 cm2 LV eccentricity index 1.0 Vena cava inferior max diameter 5 mm TAPSE 23 mm Cardiac catheterization 8 weeks: mPAP 15 mmHg (PAP range 26/9 mmHg). Wedge 6 mmHg PVR 1.3 Wood units (107 dyn/s/cm5).. Effect of vitamin C on laboratory values: Hb at diagnosis 74 g/L 8 weeks: 140 g/L (+89%) Time series Data for our graph was published in Table 1, the data are extracted above. NOTES 36 Kurnick (2023) [91] https://pubmed.ncbi.nlm.nih.gov/37650076 https://doi.org/10.1016/S0735-1097(23)02958-3 (meeting abstract) Patient 25 y female, USA History of iron deficiency anaemia secondary to menorrhagia. Duration of the symptoms before hospital 5 months shortness of breath and generalized weakness. ECHO was “unremarkable” (see below). Signs and symptoms 2 weeks progressive weakness, shortness of breath, myalgia, arthralgia. Main findings On admission, HR 123, BP 131/93 mmHg. O2 saturation 100% on room air. ECG revealed sinus tachycardia with right axis deviation. CT angiogram of the chest ruled out pulmonary embolism; but revealed significant right heart strain. ECHO showed sPAP 71.1 mmHg with severely dilated RV and RA. TAPSE 9.5 mm. Non-collapsible inferior vena cava dilated to 3.0 cm. ECHO 4 months prior to admission: normal ventricles and papillae, normal size RV. Normal TAPSE 23 mm. HD4. cardiogenic shock, HR 45, BP 77/56 mmHg, O2 saturation 69% on room air.. Two episodes of cardiac arrest with pulseless electrical activity but return of spontaneous circulation. HD5. Catheterization mPAP 48 mmHg (63/43/48 mmHg) Wedge pressure 13 mmHg. PVR 16 Cardiac output 2.2 L/min Cardiac index 1.6 L/min/m2. HD14 Catheterization mPAP 39 mmHg Wedge pressure 19 mmHg. PVR 4.3 WU Cardiac output 4.6 L/min Cardiac index 2.8 L/min/m2. On admission Hb 71 g/L pro-BNP 330000 pg/mL mildly elevated troponin Vitamin B1 and D level were within normal limits HD5 AST 136, ALT 71 37 Drugs in hospital Norepinephrine , Dobutamine, Milrinone Other vitamins and minerals Diet before the event Severely restricted diet lacking fruits and vegetables, mostly consuming chickpeas Vitamin C treatment 2 g intravenous vitamin C per day. Discharged on oral vitamin C 1 g daily Effect of vitamin C HD23 Repeat ECHO revealed the resolution of right ventricular dilation with complete resolution of RHF and PH. Collapsible inferior vena cava measuring 14 mm. TRPG 16 mmHg. HD23 Catheterization PAP 36/9 mmHg [we calculate mPAP = 24 mmHg] Wedge pressure 9 mmHg. Repeat ECG showed resolution of right axis deviation. NOTES We contacted John Sabu to ask for more details (email 2023-3-15, 20239-26 and 2023-9-29). We did not receive any response. We were able to contact Adam Kurnick (email 2023-3-15) but we were unable to get any additional information of the case. The case was first published as an abstract (above), but a final report was published before we finished the manuscript and details were extracted from the report (above) 38 Mehta (1996) [92] https://pubmed.ncbi.nlm.nih.gov/8607903 Patient 40 y woman with anorexia nervosa. She had been in psychiatric care and was on sertraline. Amenorrheic since the birth of her 5 y child; breastfed this child until 6 months prior to presentation. Duration of the symptoms before hospital 3 months Signs and symptoms Arthralgia, myalgia, weakness, fatigue for 3 months. 1 week prior to presentation, shortness of breath and a purpuric rash on her legs. Main findings On the lower extremities, there were erythematous tender nodules, diffuse perifollicular purpura, and an ecchymosis. Tenderness on palpation in knees, ankles and feet. Ankles showed moderate synovial swelling, warmth, and pain on palpation. Height 157.5 cm, and weight 44 kg, BMI 17.7. Heart sounds normal Hb 118 g/L. ESR 12 mm/h. CXR and CT showed diffuse interstitial prominence and multiple intraparenchymal nodules with size <1 cm. Pulmonary function testing showed DLCO 53% and vital capacity of 70%. Bronchoscopic evaluation led to severe bleeding and hypotension, and fluid resuscitation thereafter led to severe anasarca. A lung biopsy showed interstitial edema. ECHO showed severe PH, with a dilated pulmonary artery, and RA and RV enlargement. Right heart catheterization showed a PAP 55/35 mmHg. Vitamin B 1178 nM (88-192) Vitamin C level 2 mg/L (11 μM). Drugs in hospital None Other vitamins and minerals Diet before the event Diet consisted of 2-4 bagels per day. Prolonged breastfeeding might also contribute to the decline in vitamin C level in the mother’s body. Vitamin C treatment Vitamin C supplementation indicates oral administration, but dose was not reported. In addition, “other supportive therapies” which were not described, but they were not corticosteroids or antibiotics. Effect of vitamin C In 1 week, her musculoskeletal, skin, and pulmonary symptoms 39 resolved. In 19 days, the CXR, ECHO, and pulmonary function test results had normalized. NOTES 40 Mertens (2011) [93] Case 3 Elie Gertner https://pubmed.ncbi.nlm.nih.gov/21185063 Patient 74 y female with no significant medical history, no smoking. Duration of the symptoms before hospital “Several months”; we translate this to >3 months Signs and symptoms Worsening exertional dyspnea. Main findings Bilateral erythematous and swollen ankles, and a purpuric rash along her right forearm. Cardiac auscultation showed grade 2/6 systolic murmur. Right heart catheterization showed severe PH with sPAP >80 mmHg. A chest CT showed a 1.5-cm consolidation in the left upper lobe. Pulmonary function test showed moderate restrictive disease with FVC 65% and FEV1 63%, and DLCO 46% of predicted. Hb 124 g/L ESR 41 mm/h Vitamin B6 and Zn levels normal Vitamin B1 slightly low, but no data Vitamin C level undetectable, <0.12 mg/dL (<7 µM). Drugs in hospital Nifedipine, self-discontinued after 1 week. Other vitamins and minerals Diet before the event She had a number of delusions about sensitivities to foods and other chemicals and limited her diet to ground beef, goat’s milk, tapioca, spring water, and vitamin B6 and vitamin A supplements. Vitamin C treatment Vitamin C supplementation 1 g/day, but route not defined. Vitamin C alone. Effect of vitamin C After 5 months, a repeat ECHO showed near complete resolution of her PH with vitamin C supplementation alone and she was asymptomatic for any cardiopulmonary symptoms. NOTES To ask for further details of the case, we contacted Elie Gertner by email on 2023-2-8 and 2023-2-23 but did not get a response. 41 Petersen (2019) [97] https://shmabstracts.org/abstract/when-life-doesnt-giveyou-lemons-a-rare-case-of-acute-heart-failure Patient 5 y boy with ASD Duration of the symptoms before hospital 2 months Signs and symptoms Fatigue, lower extremity pain, petechial rash, weight loss, Refusal to walk for 1 week. Main findings HR 160 bpm, BP 93/68 mmHg, respiratory rate 30/min. SpO2 normal on ambient air. Cardiac auscultation S3 gallop, no jugular venous distension. ESR 33 mm/h. After intravenous fluids, he became acutely hypotensive and hypoxic necessitating oxygen via a face mask and vasopressor support. Lower limb Doppler ultrasound excluded DVT. CTA normal. ECHO indicated PH, a severely dilated RV with systolic dysfunction, and elevated right-sided pressures. Erythrocyte sedimentation rate 33 mm/h Vitamin C level undetectable. Drugs in hospital Vasopressor Other vitamins and minerals Diet before the event Extremely restricted diet due to oral aversion, but no further description of the usual diet is described. Vitamin C treatment Vitamin C intravenously, but dose not reported. Effect of vitamin C administration Immediate improvement in PAP. In 1 week, normalization of strength and gait. In 2 weeks, complete reversal of RV dysfunction. NOTES We were able to contact Dr. Liz Petersen, who responded 2023-2-26 that the data were no more available. 48 Quinn (2022) [98] Benjamin Frank Moore https://pubmed.ncbi.nlm.nih.gov/36389378 Patient 6 y boy with ASD Duration of the symptoms before hospital 3 months Signs and symptoms 1-week prior to presentation, inability to bear weight on the left leg. Parents brought him to clinic in a stroller. Weight loss 5% in 3 months. Main findings During upper endoscopy the patient developed bradycardia, hypotension, cardiac arrest. CT excluded pulmonary embolism. Echo shortly post-arrest showed signs of PAH including elevated TRV and severely diminished RV function, and significant RV hypertrophy, suggesting that PAH predated the cardiac arrest. “Other diagnoses on the differential for the cardiac arrest that were excluded included tachyarrhythmia (no evidence on cardiac monitor during the event), cardiac tamponade (no evidence on echocardiogram or clinically), pulmonary embolism (normal CT scan), and underlying primary neurologic or genetic/metabolic disorders. Given this, scurvy-associated PAH was thought to be the primary contributor to his arrest.” Vitamin B1 55 nM (70–180) Vitamin A 15 µg/dl (19–77) Vitamin D <3.5 ng/ml (30–96l) ferritin 16.6 ng/ml (>20) Fe saturation 12% (>20%) Se 43 ng/mL (70–150) Zn 0.39 µg/mL (0.6–1.2). Vitamin C level undetectable, <0.1 mg/dL (<0.6 µM). Drugs in hospital iNO on HD9 Sildenafil on HD9 Other vitamins and minerals Vitamin B1 within 24 h of admission to pediatric ICU. Multivitamin within 24 h of admission to pediatric ICU. Se started on HD2. Discharged with multivitamin, Zn, Fe. Diet before the event Diet had been restrictive after choking on a French fry at 2 y of age, and consisted of a nutritionally complete supplemental beverage and candy. In 6 months prior to presentation, he further narrowed diet to only chocolate peanut butter cups and water. Vitamin C treatment Vitamin C within 24 h of admission to the pediatric ICU Effect of vitamin C administration HD9: Repeat ECHO showed improvement in RV dilation and TR. At follow-up 3 months, no signs or symptoms of cardiac 49 dysfunction, and no evidence of PAH on repeat ECHO. Sildenafil was discontinued 6 months after the cardiac arrest and a follow up ECHO 3 months off sildenafil remained stable: normal endsystolic septal position, normal RV size, and no RV hypertrophy. Time series Dr. Frank kindly provided us with the data for our time series graph, see below. NOTES We were able to contact Benjamin Frank, who responded 2023-29 to our question for the ECHO data: We were also able to contact Jaime Moore, who responded 20233-21 to our question about vitamin C doses and the vitals: “1) Regarding the details of our patient's separate Vitamin C supplementation: -Within 24h of the admission, he received an initial dose of enteral ascorbic acid 250mg crushed tablet delivered via nasogastric tube -The following day, he received both a dose of enteral ascorbic acid 250mg crushed tablet via nasogastric tube and a dose of IV ascorbic acid 100mg -For the next 6.5 days, he received IV ascorbic acid 100mg twice a day -For the next 20 days, he received enteral ascorbic acid 125mg once a day 2) Baseline HR, BP, and respiratory rate: It was documented on more than one occasion that because of the patient's (autism-related) behaviors, BP and HR were difficult or 50 42 25 16.90% 33.80% 41.30% 0.4 1.5 1.6 1.2 1.1 1.1 2.3 1.1 0.9 1 Echo Timing/Parameters  Shortly After Arrest on ECMO  9 Days Post Arrest   ~4 Weeks Post Arrest (Fig 1 B) on sildenafil  9 Months Post Arrest off sildenafil  Mean pulmonary artery pressureK K K Additional Parameters from Table 1 Below Evidence of pericardial effusion (Y/N) K NK NK NK NK Right ventricular fractional area changeK K Tricuspid annular plane systolic excursionK K K Tricuspid valve regurgitationK 3.3 m/sK 2.6 m/sK 2.3 m/sK 2.3 m/sK EccentricityK RV systolic to diastolic duration ratioK impossible to obtain during routine outpatient clinic visits. On the date of his admission to the hospital, the first recorded full set of vitals were: HR: 138 BP: 118/89 RR: 28 I would interpret these cautiously as this likely reflects some degree of patient anxiety and thus, inflation, compared to what they might be in an environment where he was calm/relaxed.” 51 Ratanachu-Ek (2003a) [99] https://pubmed.ncbi.nlm.nih.gov/14700174 https://www.researchgate.net/publication/8938594 Patient 1 y 9 month boy. This is one of 28 cases reported, the next case is one from the same series. Duration of the symptoms before hospital No data Signs and symptoms Fever, limb pain and clinical right-sided heart failure [we infer that this indicates edema in this context]. Main findings “Did not have any neurological signs of beriberi and diuretic effects from thiamine treatment” (p S738) Pulmonary hypertension was diagnosed by ECHO (p S736) “Moderate pericardial effusion” “Two cases of pulmonary hypertension and right-sided heart failure diagnosed by echocardiogram without available investigation for vitamin B1 level. Both cases of pulmonary hypertension did not have any neurological signs of beriberi and diuretic effects from thiamin treatment. So the pulmonary hypertension might not relate to thiamin deficiency” (p S738). Drugs in hospital None Other vitamins and minerals Vitamin B1, but dose not mentioned Diet before the event “In the present study, the dietary history revealed that intakes of fresh vegetables and fruit or fruit juice were inadequate” (p S737). “fed with well-cooked foods and small amounts or no vegetables and fruits” (p S734). In all, there were 28 scurvy cases, but the above statement seems to apply also to the 2 cases we include in our study. Vitamin C treatment 0.15-0.3 g/d vitamin C. This is one of 28 cases, with description that “underweight cases were supplemented with multivitamins and iron was supplemented in cases suspected of iron deficiency anemia” but there is no specific description for this case. Effect of vitamin C “Clinical signs of limb pain and heart failure improved after a few days” Normal ECHO was recorded 1 week after treatment (p S736). “The result of vitamin C treatment in this study was dramatic with gradual improvement of all physical signs in a few days” (p S738). “There was no previous report on pulmonary hypertension in scurvy but two cases in the present study responded to vitamin C treatment” (p S738). NOTES We were able to contact Suntaree Ratanachu-ek, who responded 2023-331: “I did not have any recollection about 2 cases of pulmonary hypertension in 28 patients in 2003, and all previous records were destroyed.” 52 Ratanachu-Ek (2003b) [99] https://pubmed.ncbi.nlm.nih.gov/14700174 https://www.researchgate.net/publication/8938594 Patient 2 y 10 month boy. This is one of 28 cases, see previous case. Duration of the symptoms before hospital No data Signs and symptoms Fever, limb pain and clinical right-sided heart failure [we infer that this indicates edema in this context]. Main findings “Did not have any neurological signs of beriberi and diuretic effects from thiamine treatment” (p S738) Pulmonary hypertension was diagnosed by ECHO (p S736) “Hypertension” but no data “Two cases of pulmonary hypertension and right-sided heart failure diagnosed by echocardiogram without available investigation for vitamin B1 level. Both cases of pulmonary hypertension did not have any neurological signs of beriberi and diuretic effects from thiamin treatment. So the pulmonary hypertension might not relate to thiamin deficiency” (p S738). Drugs in hospital None Other vitamins and minerals Vitamin B1, but dose not mentioned Diet before the event “In the present study, the dietary history revealed that intakes of fresh vegetables and fruit or fruit juice were inadequate” (p S737). “fed with well-cooked foods and small amounts or no vegetables and fruits” (p S734). In all, there were 28 scurvy cases, but the above statement seems to apply also to the 2 cases we include in our study. Vitamin C treatment 0.15-0.3 g/d vitamin C . This is one of 28 cases, with description that “underweight cases were supplemented with multivitamins and iron was supplemented in cases suspected of iron deficiency anemia” but there is no specific description for this case. Effect of vitamin C “Clinical signs of limb pain and heart failure improved after a few days” Normal ECHO was recorded 1 week after treatment. “The result of vitamin C treatment in this study was dramatic with gradual improvement of all physical signs in a few days” (p S738). “There was no previous report on pulmonary hypertension in scurvy but two cases in the present study responded to vitamin C treatment” (p S738) Hypertension was slowly improved in 2 weeks. NOTES We were able to contact Dr. Ratanachu-ek, who responded 2023-3-31: “I did not have any recollection about 2 cases of pulmonary hypertension in 28 patients in 2003, and all previous records were destroyed.” 53 Sakamornchai 1 (2022a) [100] Oraporn Dumrongwongsiri https://pubmed.ncbi.nlm.nih.gov/36337659 Patient 6y boy with ASD. The same report published 2 cases, see also the next. Duration of the symptoms before hospital 2 months. Signs and symptoms Progressive bilateral knee swelling and refused to walk for 2 months. Progressive dyspnea for 1 day. Main findings He was pale and had respiratory distress. Left leg was swelling and limited movement due to pain. Corkscrew hairs were presented over the body. HR 130 bpm, BP 107/78 mmHg, respiratory rate 48/min. SpO2 90% on room air, corrected with 10 L/min oxygen via face mask. ECHO showed TR with TRPG of 80 mmHg and D-shape LV. He was diagnosed with severe PAH, but wedge pressure and PVR were not published. “No evidence of other causes of PAH such as congenital heart disease, pulmonary embolism, and malignancy was found”, but no further examinations are described to exclude them. Hb 70 g/L MCV 60 fL Fe 14 µg/dL (normal 50-120) Transferrin saturation 4.4% (>16%) Ferritin 41.5 ng/mL (7-140) 25-OHD 16.2 ng/mL (20-100) Folate 4.6 ng/mL (4-20) Vitamin C level undetectable Drugs in hospital Inotropics Pulmonary vasodilator (not specified) Other vitamins and minerals Multivitamins, vitamin D, Fe, folate and “oral nutritional supplement” were continued after discharge. Diet before the event Meals consisted of rice porridge and boiled eggs. Some biscuits were provided as a snack. Never drank milk for 2 y and refused red meat, fruit, and vegetables. Vitamin C treatment 0.3 g/day of vitamin C was given via oral route since the 1st day of admission. Effect of vitamin C Gradually recovered from respiratory distress and could be discharged in 13 days. 1-month follow-up visit after discharge showed that he was able to mobilize both lower extremities without pain and had no dyspnea while doing the activity. 54 ECHO at 2 months after discharge showed no evidence of PAH and the pulmonary vasodilator could be weaned off. NOTES To ask for further details of the case, we contacted Oraporn Dumrongwongsiri by email on 2023-2-8 and 2023-2-23 but did not get a response. 55 Sakamornchai 2 (2022b) [100] Oraporn Dumrongwongsiri https://pubmed.ncbi.nlm.nih.gov/36337659 Patient 5 y boy with ASD, allergic rhinitis, and snoring. The same report published 2 cases, see also the previous. Duration of the symptoms before hospital 2 weeks Signs and symptoms Progressive dyspnea and refused to walk. Main findings Limited range of motion of joints due to pain. No scorbutic rosary and no corkscrew hairs. HR 136 bpm, BP 110/60 mmHg, respiratory rate 50/min. Chest X-ray showed cardiomegaly, normal pulmonary blood flow and no pulmonary congestion. ECG showed right axis deviation and low QRS voltage. ECHO showed moderate to severe TR with TRPG 80 mmHg, RA and RV enlargement with D-shape LV, impaired RV systolic function, no evidence of intra-cardiac shunt. “PAH was diagnosed”, but wedge pressure and PVR were not published. Hb 99 g/L MCV 54.2 fL Fe 20 µg/dL(normal 50-120) Transferrin saturation 4% (>16%) Ferritin 7.5 ng/mL (7-140) 25-OHD 6.02 ng/mL (20-100) Vitamin B1 49.2 µg/L(28-85) Folate 3.2 ng/mL (4-20) Vitamin C level undetectable Drugs in hospital Pulmonary vasodilator (not specified) Other vitamins and minerals A single dose of 100 mg vitamin B1 intravenously. 10 l/Multivitamins, Fe, folate supplement were given and continued after discharge. Diet before the event Only rice porridge without any meat for 1 y, and he just started having some amount of boiled egg for 1 week. He usually drank 2 L/day of plain UHT milk. Refused fruit and vegetables and did not receive any vitamin or mineral supplementation. Vitamin C treatment 0.3 g/day of vitamin C orally. Effect of vitamin C Symptoms improved dramatically the next day after vitamin C, and he was able to wean himself off respiratory support, and an ECHO revealed that his PH had improved. Discharged on HD5. 56 ECHO at 3 months after admission showed no PH. NOTES To ask for further details of the case, we contacted Oraporn Dumrongwongsiri by email on 2023-2-8 and 2023-2-23 but did not get a response. 57 On 2023-3-30 we received further data from Leong Ming Chern: ################## I have extracted these data from our echocardiogram recordings. Column1 15/10/2019 21/10/2019 31/10/2019 04/02/2020 Dominant RV Yes Yes No No Peak TR gradient 75 60 40 12 LV eccentricity 2.05 1.4 1.02 1.01 RV FAC 18.7 11.9 52.7 51.1 Pericardial effusion Yes Yes No No Thank you. MC Leong ################## 64 Ueki (2022) [104] https://pubmed.ncbi.nlm.nih.gov/35942728 Patient 11 y boy with ASD Duration of the symptoms before hospital 3 months Signs and symptoms Fatigue, myalgia, arthralgia of the knees, difficulty ambulating. Weight loss 4.4 kg in 5 months Main findings Dry skin, mild swelling of the knees, and limited range of movement at the knees and pelvis because of severe muscular pain. CXR, ECG, and ECHO demonstrated RV volume overload (% of RV end diastolic volume index; 136.5) with mild PH and TRV 2.9 m/s HR, BP, and SpO2 saturation were within normal ranges. Hb 68 g/L MCV 67 fL Fe 250 μg/L (normal 400–1880) BNP 26.9 pg/mL (<18) CRP 34 mg/L D-dimer 3.77 mg/L (<1.0) Vitamins B1, B12, folate, Se, Zn all within normal range Vitamin C level undetectable, <0.2 μg/ml (<1 μM). Drugs in hospital None Other vitamins and minerals Oral Fe daily for 10 days. Thereafter “iron supplementation for 3.5 months” but doses were not reported. Diet before the event Selective diet, including pancakes, apple juice, milk, bananas, and boiled eggs at home. A very minimal amount of vegetables, meat, and fish from his school lunches and had never taken any nutritional supplements Vitamin C treatment “1 g intravenous vitamin C for 10 days. Thereafter, oral 0.3 g/day vitamin C for 3.5 months. Then vitamin C was stopped, but plasma level decreased below detection and thereafter 0.2 g/day was continued”. See NOTES. Effect of vitamin C At discharge (following 10 days of intravenous vitamin C treatment), there was almost complete resolution of pain, and the patient was able to ambulate without assistance” Abnormalities associated with pulmonary hypertension on ECG and ECHO improved following 3.5 months of oral vitamin C Effects of vitamin C on laboratory values: Hb at diagnosis 68 g/L At discharge: 97 (+43%) 4 months: 141 (+107%) BNP at diagnosis 26.9 pg/mL 65 At discharge: 15.8 pg/mL (-41%) 4 months: 6.0 pg/mL (-78%) CRP at diagnosis 34 mg/L At discharge: 2.8 mg/L (-92%) 4 months: 0.4 mg/L (-99%) D-dimer at diagnosis 3.77 mg/L At discharge: 0.72 (-81%) 4 months: <0.25 (-93%) IL-6 at diagnosis 38.08 pg/mL At discharge: 11.08 (-71%) 4 months: 7.61 (-80%) IL-8 at diagnosis 15.53 pg/mL At discharge: 12.53 (-19%) 4 months: 201.67 (+1200%) IL-18 at diagnosis 104.70 pg/mL At discharge: 155.29 (+48%) 4 months: 201.94 (+93%) NOTES We were able to contact Masahiro Ueki and received the following reply on 2023-3-8. “In our patient, he was treated with 1000mg of vitamin C intravenously for initial 10 days. Following resolution of muscle pain and inflammation, 300mg of vitamin C was administered orally. At 3.5 months, abnormalities associated with pulmonary hyper-tension on ECG and UCG improved. I stopped vitamin C supplement at 6 month, whereas his serum vitamin C level decreased below detection without any symptoms following 3 months. After this event, He continues 200 mg of vitamin C supplement.” We received the following addition on 2023-3-10. “We evaluated PH by tricuspid valve regurgitation. At diagnosis, velocity of Tr was 2.9 m/s. At 3.5 month, velocity of Tr reduced to 2.5 m/s. I'm sorry that TAPSE was measured only at 3.5 months. TAPSE at 3.5 month was 21mm. Right ventricular outflow tract diameter (RVOTD) was measured 66 sequentially. RVOTD at diagnosis was 23.6mm (he is suffered from mild dehydration), and 26mm at 3.5 month. On 2023-3-23: “Changes in vital signs were not significant during the treatment. At diagnosis/ hospital admission HR 85 BP 89/52 RR 18 At discharge HR 97 BP 100/59 RR 18 At 3 months HR 93 BP 107/59 RR 16” 67 Valencia (2022) [105] Melody Duvall https://pubmed.ncbi.nlm.nih.gov/35969659 Patient 19 y male. Crohn's disease, primary sclerosing cholangitis, autoimmune hepatitis, decompensated cirrhosis had progressed over 6 y to end-stage liver disease. The patient underwent liver transplantation. An ECHO performed at another hospital 1 y before transplantation showed RV pressure >½ systemic, normal biventricular size and systolic function, and normal valvular function. Duration of the symptoms before hospital Signs and symptoms Postoperative ECG normal. 24 h after transfer to the ward (postop day 2), the patient developed persistent sinus tachycardia (rate, 110–130 beats/min) and hypoxia with escalation of his oxygen support to 4 L/min of oxygen via nasal cannula. Main findings CXR demonstrated retrocardiac opacification, mild interstitial edema, trace pleural effusions. Became progressively more tachycardic, tachypneic, and hypoxemic, requiring 5 L/min of nasal cannula oxygen to maintain SpO2 > 90%. Hospital emergency call for pediatric ICU-team bedside assistance was activated on postop day 3. Upon arrival of the ICU team, the patient developed bradycardia, loss of consciousness, and pulselessness and was in pulseless electrical activity arrest. ECMO team was emergently activated. Echo obtained prior to completion of ECMO cannulation demonstrated mildly depressed LV function, severely depressed RV function, RV dilation, and RV hypertension (RV pressure 2/3 systemic; RV pressure ~55 mm Hg plus the RA v-wave, while noninvasive systolic blood pressure 80 mmHg). No pericardial effusion, no evidence of pulmonary embolism at the bifurcation of the main or proximal branch pulmonary arteries. TRV 4.84 m/s After 220 min resuscitation, an adequate circulation was achieved. Laboratory results prior to cardiac arrest Hb 93 g/L Platelet 65 postoperative day 2 Hb 79 g/L Platelet 6 Cardiac catheterization: mPAP 77 mmHg (right) and 75 mmHg (left) (in their Supplement) PVR 536.6 dynes/s/cm-5 = 6.7 Wood units (in their Supplement) Wedge pressure 30 mmHg (right) and 31 mmHg (left) (in their Supplement) 68 On day 12 of ECMO, after 72 hours without any bleeding, he was given IV epoprostenol... On day 15 of ECMO, epoprostenol was discontinued. Other medical therapies included use of low-dose epinephrine and macitentan, at an enteral dose of 5 mg daily. “At the time, we also considered the possibility of vitamin C deficiency as an associated causal factor in the development of severe PAH, since vitamin C deficiency is a complication of Crohn's disease, even in patients with disease remission. We did prescribe vitamin C in this patient: we used high dosing via parenteral nutrition and eventually enterally.” (p e446) The blood level of vitamin C was measured 7 weeks after the cardiac arrest event, and it was severely low (<5 μM). Drugs in hospital Epoprostenol Milrinone Sildenafil Epinephrine Macitentan Other vitamins and minerals Diet before the event Not described, and may be a secondary issue for this particular patient Vitamin C treatment Vitamin C initially intravenously and thereafter orally. Day of starting is not described, and doses not described (only “high dosing via parenteral nutrition and eventually enterally”) Effect of vitamin C “The patient underwent ECMO decannulation after 29 days and was solely supported by the paracorporeal lung-assist device. It should be noted that prior to removing the patient from ECMO, aggressive, serial bronchoscopies were required to ensure patent airways for gas exchange. Additionally, a PA catheter was placed for evaluation of readiness for decannulation from the paracorporeal lung-assist device. PA pressures ranged from 35/25 to 45/30 mm Hg (mPAP, 30–35 mm Hg) (<½ systemic)” He was weaned from sildenafil 5 months later and from macitentan 12 months later. Follow-up echocardiogram at 21-month post-transplant demonstrated low RV pressure and qualitatively normal RV function. His follow-up vitamin C level at the time of pulmonary hypertension resolution had normalized. NOTES The report is confusing. “The blood level of vitamin C was measured 7 weeks after the cardiac arrest event” (p e446), which corresponds to 49 days. 69 On the other hand, “The patient underwent ECMO decannulation after 29 days and was solely supported by the paracorporeal lung-assist device… decannulated from the paracorporeal lung-assist device after 15 days (3-d post-ECMO decannulation). TTE thereafter demonstrated mild RV hypertension (<½ systemic) and normal biventricular systolic function.” It is not clear how the 49 day vitamin C measurement relates to the 32 day (=29+3) decannulation from paracorporeal lung assist device. The time of starting vitamin C is not described. Therefore the role of vitamin C in the recovery from PH remains obscure in the report. To ask for further details of the case, we contacted Melody Duvall by email on 2023-2-8 and 2023-2-23 and 2023-3-4 but did not get a response. 70