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Abstract
Background Hypothermia is becoming a common treatment for newborns with hypoxic ischaemic encephalopathy. Cerebral metabolic effects have been studied extensively. However, acute effects on peripheral microcirculation are unknown. The effects of therapeutic hypothermia on peripheral microcirculation assessed by side-stream dark field (SDF) imaging technique are presented.
Methods Peripheral microcirculation was assessed in seven newborns undergoing selective head-cooling treatment with SDF imaging video recordings during core temperature 34°C, and then after re-warming at 37°C, and also in seven control patients with rectal temperature 37°C. Microvascular flow index (MFI) and per cent of vessels with sluggish flow were determined by using appropriate software.
Results Sluggish microcirculation was observed during hypothermia compared with controls. MFI and per cent of vessels with sluggish flow returned to normal after re-warming.
Conclusions The results of this small group of newborns going through therapeutic hypothermia suggests that microcirculation is effected with this treatment. Whether this finding has other clinical impacts requires further research.
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Introduction
Therapeutic hypothermia is being used more and more frequently for treatment of newborns with moderate to severe hypoxic ischaemic encephalopathy (HIE), with promising results to avoid severe neurological sequela of perinatal asphyxia. Large groups of studies have provided short- and long-term outcome results of newborns exposed to selective head cooling, or total body cooling, including short-term side effects and long-term neuro-developmental outcome.1–3 Acute adverse effects have generally been summarised as sinus bradycardia, hypotension requiring inotropic support, thrombocytopenia, persistent pulmonary hypertension, hyperviscosity and decreased drug clearance,3 which are all manageable by supportive measures rarely requiring treatment discontinuation.
However, very little data is available in the literature about the effects of hypothermia on peripheral microcirculation.
Microcirculation mainly reflects the capillaries less than 100 μm in diameter, and is considered the main source for tissue oxygen and nutrient delivery. Side-stream dark field imaging (SDF) technique is a non-invasive method used to investigate microcirculation by a video microscope. Green light (530 nm wavelength) emitted from a hand-held device penetrates 1–3 mm depth of skin or mucosa, and is absorbed by haemoglobin in red cells in the capillaries, the movement of red cells in the microcirculation is recorded by a video microscope with five times magnification. The recordings are analysed offline with appropriate analysis software to determine microvasculatory flow, vessel density, per cent of vessels with different flow patterns. It has been used in adults and newborns with different disease states to observe microcirculatory effects of the clinical conditions and medications.4 The site of investigation is generally the sublingual capillary network in adults and children, and axilla in newborns.
In this group of newborns with HIE, the effects of selective head cooling with mild systemic hypothermia on peripheral microcirculation was investigated by SDF technique. Control patients who were admitted for hyperbilirubinemia with 37°C rectal temperature and no other disease were also assessed for microcirculation. The study techniques were approved by the hospital ethics committee, and informed consent was obtained.
Methods
Selective head cooling was administered to newborns less than 6 h of age with moderate to severe HIE based on clinical scoring, and amplitude-integrated EEG traces with Olympic-Coolcap system (California, USA) for 72 h. Rectal temperature was aimed to be kept at 34°C.
Microcirculation was assessed during cooling right before re-warming at the 72nd h of treatment, and after re-warming, when the rectal temperature reached 37°C which corresponded to 6 h after discontinuation of hypothermia. None of the patients had circulatory problems, polycythemia, anaemia or sepsis during assessment. Control patients of the same age (72 h) were included.
Microcirculation measurements
Microcirculation was assessed by Microscan (Microvision Medical, Nl) device by SDF imaging technique from the axillary area in the controls who had rectal temperature 37°C, and in newborns receiving selective head-cooling treatment at rectal temperatures 34°C, and after re-warming at 37°C. Three to five video recordings, 20 s each, were obtained and analysed offline with special software AVA 3.0.
Microvascular flow index (MFI) which is an arbitrary value for blood flow in vessels <100 µm in diameter was calculated based on flow assessment of the vessels as described below.5
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0: No flow
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1: Intermittent flow
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2: Sluggish flow
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3: Continuous flow
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4: Hyperdynamic flow
The vessels were analysed according to flow pattern, and the per cent of vessels with sluggish flow were also determined. Perfused vessel density (PVD) (mm/mm2) was calculated by the software.
SPSS 11.5 was used for statistical analysis, the difference between microcirculation values was assessed by Wilcoxon test. All results are expressed as median and range.
Results
Microcirculation assessments were obtained on seven controls and seven newborns receiving selective head-cooling treatment. Patients had gestational age (GA) between 37 and 39 weeks, and birth weight between 2300 and 3900 g, whereas, controls had GA between 37 and 39 weeks, and weighed between 3000 and 3700 g. MFI values and ratio of vessels with sluggish flow in patients during hypothermia and after re-warming are shown in figure 1. The MFIs representing microcirculatory flow were lower during cooling compared with the values after re-warming. MFI increased significantly after re-warming (cooling: 2.23 (1.76–2.71) and 3 (2.8–3.16) after re-warming, p=0.018), and was significantly lower during cooling than in controls (3 (3–3.25) p=0.01), with no difference after re-warming (p=0.25). The percentage of vessels with sluggish flow was higher during cooling, 95.34%, (2%–97%), and decreased significantly after re-warming, 0.7%, (0–3.49) p=0.028. Sluggish flow was not observed in the controls. PVD was not different during and after cooling; 13.54 (10.9–15.16) mm/mm2 and 14.3 (10.8–16.8) mm/mm2 p=0.2. PVD in controls was 16.7 (14.8–18.7) mm/mm2, and it was higher than patients during cooling p=0.01, but similar to them after re-warming p=0.08. Examples of microcirculation video recordings during and after hypothermia are available to view as online supplemental files.
Changes in microcirculation during hypothermia and re-warming. MFI, Microvascular flow index; Pt, Patient. This figure is only reproduced in colour in the online version of this paper.
Discussion
Hypothermia has become a frequently used treatment for neuroprotection both in adults and children, including newborns, who suffer from trauma, stroke or HIE. Most of the neuroprotective effects are thought to be due to the slower metabolism and decreased inflammation, as well as decreased apoptosis during hypothermia.1 Since neuroprotection is the priority, the focus has been the cerebral effects in most of the studies concerning hypothermia. The attention to peripheral effects has been limited to acute adverse events requiring intervention, leaving peripheral microcirculation neglected.
In animal research, effects of systemic hypothermia on local soft tissue trauma in mice, impact on oxygenation, microregional perfusion in rat tumours, in vivo effects during extracorporeal circulation in hamster dorsal skinfold have been looked at, and the studies have reported decreased and affected microcirculation.6–8
On the other hand, human research has been focused primarily on adults going through hypothermic cardiopulmonary bypass (CPB). Boldt et al9 have reported decreased microcirculatory flow assessed with laser doppler on forearm and forehead in patients going through hypothermic CPB. Bauer et al10 have found no change in microcirculation in adults during uncomplicated hypothermic CPB measured by sublingual orthogonal polarisation spectral imaging, which is a different form of SDF imaging. Elbers et al11 have noted cessation of flow in sublingual vessels smaller than 20 μm in diameter during hypothermic circulatory arrest of adult patients by SDF technique.
This is the first study investigating peripheral effects of cooling down to 34°C rectal temperature together with head cooling in newborns with HIE measured with SDF technique. In this small group, marked decrease in microcirculatory blood flow was noted during hypothermia assessed from axilla. It may be speculated that this finding is due to hyperviscosity which is likely to occur during hypothermia. We were not able to measure viscosity in our group which might be considered as one of the caveats of the study. Whether this finding also represents decreased microcirculatory flow in other organ systems, and whether this has any clinical significance for the patient is unclear. More data accumulation on the same group of patients will certainly be helpful to reach reliable conclusions. The PVD in controls was higher than patients during hypothermia, but similar to values of patients after re-warming, although the values were not statistically different in the patient group during and after hypothermia. These results may suggest that PVD measured at axilla is a less affected aspect of microcirculation during hypothermia, but again, this requires further investigation.
In conclusion, this study suggests that mild systemic hypothermia has some reversible effects on peripheral microcirculation. These findings should be kept in mind while taking care of newborns during therapeutic hypothermia, and careful documentation regarding peripheral effects of cooling is particularly essential. It should also be noted that these are the results from mild systemic hypothermia during selective head cooling. We still do not have information about peripheral microcirculation during whole-body cooling, which is another target of research.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online movie 1
- Data supplement 1 - Online movie 2
Footnotes
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Contributors Nilgun Altuntas, Ebru Kazanci, Sezin Unal, Esra Onal, Canan Turkyilmaz, Yildiz Atalay.
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.