Raman, S; (2017) Investigation of oxygen targets and hypoxic adaptation in paediatric critical illness. Doctoral thesis , UCL (University College London).

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Abstract

Background: The effect of varying oxygen tension on the outcome of critically ill patients is contentious. Many interventions employed in the intensive care unit aimed at increasing oxygen delivery can cause harm. During the natural history of critical illness, adaption to tissue hypoxia may occur to a greater or lesser extent. I used the principle of Near Infrared Spectroscopy (NIRS) with a vascular occlusion test to investigate forearm muscle oxygen consumption. / Methods: The relationship between arterial oxygenation and mortality in critically ill children was explored with a retrospective observational study, a national survey and a systematic review in chapter 3. Chapter 4 describes a study of Near infrared spectroscopy with a vascular occlusion test (NIRS VOT) in children with suspected mitochondrial disease. The aim was ascertain if NIRS VOT as a technique is able to reflect tissue oxygen consumption. Chapter 5 covers the Young Everest Study 2. Healthy volunteers (8-16 years) who travelled to Nepal and trekked to 3525 meters altitude were tested at two altitudes (sea level and 3525 meters). The aim was to investigate the physiological response to a hypobaric hypoxic environment including the NIRS VOT. Chapter 6 covers studies conducted on critically ill children admitted to the PICU in GOSH. These include serial NIRS VOT study, an in-vivo measure of oxygen consumption of peripheral blood mononuclear cells and the expression of oxidative phosphorylation (OXPHOS) genes changes in the first 48 hours after admission to the PICU in children with meningococcal septic shock. / Results: Chapter 3: The epidemiological study of the children admitted to the intensive care unit showed that 40 children had a P aO2 of less than 20 mmHg (2.6 kPa) out of a total 7751 admissions in a 9 year period. Of these, 33 children survived to hospital discharge. There was a U shaped relationship between arterial oxygen tension and mortality. The results from the survey showed a varied practice. Of the total, 21 respondents (42%, 95%CI : 29.3 55.7%) stated that they do not follow specific P aO2 targets. Of the rest, as equal number (21, 42%) aimed for targets between 8.1 (61 mmHg) and 10 kPa (76 mmHg). Only 8(16%) aimed for what would be considered a normal range (10.1 13kP a). A majority of the units (96%) reported having an alarm target on their oxygen saturation monitor. However, 73% of the respondents worked in units that did not have an oxygen weaning protocol for mechanically ventilated patients. In acute respiratory distress syndrome, cardiac arrest and sepsis, there was a tendency to aim for lower P aO2 (<10 kPa) as the F iO2 increased. Following traumatic brain injury and in pulmonary hypertension, there was a propensity to aim for normal P aO2 (10.1-13 kPa) even as the F iO2 rose (28-33% when F iO2 >0.4). The systematic review identified 11 studies (n=5280) related to hypoxia with combined odds ratio (OR) for death of 3.13 (95%CI: 1.79-5.48, p <0.001) compared to normoxia. Six studies (n=2012) investigated the effect of hyperoxia and suggest no e↵ect on mortality compared to normoxia: OR 1.15 (95%CI: 0.42-3.17, p = 0.77). / Chapter 4: A DropTOI value of 14 was noted to have the least crossover between the mitochondrial disease group and controls. This was empirically set as the cutoff for the 2x2 table. The Fisher exact test statistic was 0.22 and showed that NIRS VOT is unable to differentiate between mitochondrial disease and controls. The NIRS VOT was able to exclude mitochondrial disease in healthy children with a high degree of certainty (positive LR - 5.66, 95%CI:0.84-38, negative LR - 0.61, 95%CI:0.47-0.80). / Chapter 5: The SpO2 at rest decreased from 99±0.79 to 89±2.54 % from London to Namche (p=0.0009). The SpO2 after exercise decreased from 93.5 ± 7.16 to 83.3 ± 5.06 % from London to Namche (p=0.008). The heart rate Z-scores at rest changed from 0.44±0.70 to 0.10±0.76 bpm (p=0.30) whilst the heart rate Z-scores after exercise increased from 1.20 ± 1.30 to 2.07 ± 1.46. Cardiac index (at rest) did not show a statistically significant change with an ascent to moderate altitude. Respiratory rate after exercise increased consistently from sea level (22.2 ± 4.4) to Namche Bazaar (27.6 ± 10.9). With a multilevel functional regression analysis, the baseline TOI was significantly lower in Namche Bazaar than London (-4.05, 95%CI: -3.23, -4.86, p <0.001). The lowest TOI was also significantly lower in Namche Bazaar (-1.95, 95%CI: -1.13, -2.76, p <0.001). The DropTOI at Namche bazaar compared to sea level was 2.1 points lower (p <0.0001). / Chapter 6: Tissue Oxygen Index varied during the first 5 days of illness. The DropTOI decreased until day 4 (3.02 lower) and showed relative increase on day 5 (0.93 lower) compared to day 1. The net routine control ratio (measured with oroboros analyser) dropped from day 1 to day 5. On the group level analysis (all five patients assessed together), with a false discovery rate (FDR) at <25% and ranked according to their Normalised Enrichment Score (NES), 1039 out of 3655 gene sets showed a decreasing profile with time. The respiratory electron transport chain gene set was ranked 75th of the 1039 gene sets. / Conclusions: The oxygen administration practices in the paediatric intensive care units in the UK vary widely. Of note, admission PaO2 has a ‘U-shaped’ relationship to mortality in children admitted to the paediatric intensive care unit. Healthy children, when exposed to hypobaric hypoxic conditions, show a tendency to decrease oxygen consumption from forearm muscle. There was some evidence that critically ill children demonstrate similar signs of early adaptive response by reducing oxygen consumption.

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