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Original articles: P Shah, S Riphagen, J Beyene, and M Perlman Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F152-F155 [Abstract] [Full text] [PDF]

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Electronic letters published:

Questioning the Criteria for Hepatic Involvement In Hypoxic-Ischemic Encephalopathy

Aylin Tarcan, Berkan Grakan, Filiz Tiker   (15 March 2004)

Hypovolemia:The Cause of Multiorgan Dysfunction

George M. Morley   (22 April 2004)

Retraction Respiration: the Multiorgan Dysfunction that Causes Ischemic Encephalopathy

George M. Morley, none   (21 May 2004)

Reply to Tarcan et al.

Prakesh S Shah, Max Perlman   (30 June 2004)

Reply to Morley

Prakesh S Shah, Max Perlman   (15 September 2004)

Response to Prof. Shah's Letter

George M. Morley   (4 November 2004)

Questioning the Criteria for Hepatic Involvement In Hypoxic-Ischemic Encephalopathy 15 March 2004
Aylin Tarcan, Neonatologist Baþkent University, Faculty of Medicine, Berkan Grakan, Filiz Tiker Send letter to journal: Re: Questioning the Criteria for Hepatic Involvement In Hypoxic-Ischemic Encephalopathy aylintarcan{at}yahoo.com Aylin Tarcan, et al.	Dear Editor We read with interest the article by Shah et al. in which the authors compared groups of neonates with good versus poor outcomes after severe perinatal asphyxia (PNA).[1] Shah et al. reported marginal differences in the incidences of kidney and cardiovascular system dysfunction, but found no differences with respect to pulmonary or hepatic dysfunction. This article raises an important point of controversy, and highlights the need for consensus on the definition of organ dysfunction. We agree with the statement of Shah et al. that our data on hepatic injury in newborns with PNA differ from their findings because different diagnostic criteria were used. Our study investigated 56 newborns who were diagnosed with severe PNA in the years 2000 through 2003. Our diagnostic criterion for severe PNA was similar to the criteria used by Shah et al. A total of 67 neonates were diagnosed with PNA during this period, but we only studied the 56 babies whose serum liver enzyme levels were measured. Our criterion for diagnosing hepatic involvement was ALT >100 U/L (twice upper-normal) with subsequent normalization of this enzyme level. According to our data, 33% of the infants with severe PNA had hepatic involvement. Severe cholestasis and coagulopathy were associated with PNA in 2 (3%) of the cases. In contrast, the criterion Shah et al. used to identify hepatic dysfunction in both their study groups (babies with good or poor outcomes after severe PNA) was aspartate transaminase (AST) or ALT >100 U/L at any time during the first week after birth. Their reported rate of liver involvement in severe PNA was 86%. In our study, we found that hepatic involvement was associated with thrombocytopenia, convulsions, intracranial pathology on central nervous system imaging, and high mortality. Several authors have shown that development of ischemic hepatitis in the critically ill patient is an indicator of poor prognosis.[3] Our results in newborn babies with PNA confirmed these findings; there was a clear association between hepatic dysfunction and mortality. We did not accept AST or lactate dehydrogenase levels as markers of liver involvement in our study. These enzymes are frequently elevated in the settings of myocardial and muscular injury or hemolysis, and such conditions/damage are frequent in PNA. Similarly, prolonged prothrombin time and elevated international normalized ratio cannot be used as markers of liver injury because these abnormalities may be detected in consumption coagulopathy.[2] Hypoalbuminemia is also inconclusive, as this can develop due to capillary leakage.[2] In our study, when we categorized the infants according to hepatic involvement (ALT >100 U/L [n=22] versus ALT <100 U/L [n=34]), we found no significant differences between the groups with respect to serum AST level, serum albumin level, prothrombin time, or international normalized ratio. The mean lactate dehydrogenase levels were significantly different. These results are further evidence that markedly elevated ALT is a specific indicator of hepatic involvement in newborns with severe PNA. Shah and co-workers also referred to an investigation by Hankins et al.[4] that was aimed at determining the extent of organ injury necessary to cause neonatal encephalopathy. The authors detected ALT elevation (1.5 times upper normal) in 35% of their newborns with severe PNA, but found that the rate of "hepatic injury" rose to 76% when the criterion was AST elevation. Another study reported the autopsy findings for 35 lethal PNA cases.[5] Severe liver pathology (defined as centrilobular necrosis and marked hemorrhage) was noted in 8 of these autopsies (23%), and mild liver changes (congestion and fatty change) were observed in 22 cases (63%).[4] The same investigators also assessed pathological findings in relation to serum transaminase levels. Fifteen of their cases had laboratory data sufficient for grading liver dysfunction. Alanine transaminase and AST were both >200 U/L in 6 of these 15 cases, and severe liver pathology was detected in 3 of these 6 infants. In conclusion, it is still not clear how liver enzyme levels correlate with clinical and pathological hepatic involvement in neonates with PNA. Until such connections are defined, it will remain difficult to accurately diagnose multiple organ dysfunction and relate it to long-term outcome in this patient group. References 1. Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004;89:F152-F155. 2. Kew MC. Serum aminotransferase concentration as evidence of hepatocellular damage. The Lancet 2000;355:591-592. 3. Vazquez P, Lopez-Herce J, Carrillo A, Sancho L, Bustinza A, Diaz A. Hepatic dysfunction after cardiac surgery in children. Pediatr Crit Care Med 2001;2:44-50. 4. Hankins GDV, Koen S, Gei AF, Lopez SM, Van Hook JW, Anderson GD. Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. Obstet Gynecol 2002;99:688-691. 5. Barnett CP, Perlman M, Ekert PG. Clinicopathological correlations in postasphyxial organ damage: A donor organ perspective. Pediatrics 1997;99:797-799.
Hypovolemia:The Cause of Multiorgan Dysfunction 22 April 2004
George M. Morley, Retired Obstetrician / Gynecologist Send letter to journal: Re: Hypovolemia:The Cause of Multiorgan Dysfunction obgmmorley{at}aol.com George M. Morley	Dear Editor The authors’ premise that neonatal multiorgan dysfunction (MOD) in HIE is caused primarily by asphyxia that reflexively shunts circulation from all body parts to the heart and brain is not very plausible. The diving reflex does not last very long. If anoxia persists, the heart and brain soon exhaust oxyhemoglobin, cardiac arrest and death (tissue necrosis) follow rapidly. If oxygenation is restored before cardiac arrest occurs, the reflex is reversed and all organs survive undamaged. In HIE, the heart and brain are parts of MOD; they are not “protected.” All these organs have grown and developed on a relatively hypoxic blood supply – the kidneys’ blood supply is the same blood that flows to the placenta to be oxygenated. If adequately perfused, they tolerate hypoxia well. It is probable that most, if not all babies in this study had repeated exposure to the diving reflex; cord compression is the most common cause of fetal distress and birth asphyxia. This is seen on the fetal monitor strip as late decelerations. Cord compression decreases fetal oxygen supply, hypoxia starts the diving reflex, the heart rate slows and blood flow is diverted to heart and brain. Cord compression is relieved during uterine diastole, fetal oxygenation returns, the diving reflex is turned off and fetal perfusion should return to normal; however, cord compression produces pathology other than hypoxia. Cord compression acts like a venous tourniquet, impeding oxygen and BLOOD flow into the child; with successive compressions, the placenta is progressively engorged and the child becomes increasingly hypovolemic. [1] The condition may stabilize when placental engorgement raises cord venous pressure enough to counter the pressure on the cord. Such newborns are hypoxic and acidotic; clinically they are “dish-rag” limp and ashen white with patches of cyanosis. They are extremely hypovolemic. Routine resuscitation, advocated by ACOG and SCOG, (ACOG Practice Bulletin 138) is to clamp the cord immediately to obtain cord pH samples and to transfer the child to a resuscitation table. This separates a very hypovolemic neonate from a large portion of its natural blood volume that is clamped in its placenta. Following ventilation, the pulmonary vessels fill with what is left of the child’s blood volume, the systemic cardiac output and blood pressure fall, and all the multiorgan dysfunctions are activated by hypotension, hypovolemia and ischemia: · Renal: Low central venous pressure triggers massive release of antidiuretic hormone and the kidneys shut down. In prolonged hypotension and hypo-perfusion, lower nephron nephrosis or cortical necrosis may occur. · Cardiovascular: Low venous return causes cardiac output and blood pressure to fall. Vasoconstrictors are used to maintain blood pressure. Transient myocardial ischemia due to hypotension may appear on the EKG. · Pulmonary: Diaphragm and other respiratory muscles lack enough perfusion to function well and are readily exhausted. The respiratory center in the brain may also be under-perfused, leading to apnea. Retraction respiration may occur. This is a reflexive effort to fill the heart with blood using negative intra-thoracic pressure. In adult hypovolemic shock, the symptom is described as “air hunger.” · Hepatic: Diminished perfusion of the gut and hence the hepatic portal vein and liver curtails conversion of liver glycogen into glucose resulting in hypoglycemia and produces other biochemical signs of liver failure. Maintenance of blood pressure in hypovolemic shock by means of vasoconstrictors does not increase tissue perfusion; it may result in infarction – necrotizing entero-colitis. At normal delivery, (no cord clamp used, no fetal distress, physiological cord closure) placental transfusion increases the child’s blood volume by a factor of 30% to 50+% [2] [3]. Normal neonatal systolic blood pressure is 80+mms Hg and the normal central venous pressure immediately after natural cord closure may be as high as 10mms Hg (13 cms water.) [4] This large additional blood volume is readily accommodated and is needed in the newly functioning lungs, gut, liver, kidneys, skin and respiratory muscles. Immediate cord clamping in the “normal” newborn may result in hypotension, hypovolemia and anemia; [5] In the compromised neonate, immediate cord clamping may result in fatality. [6] Despite all of the children in this study having signs and symptoms of birth asphyxia, there is no evidence that their injuries are hypoxic in origin; the ischemia and ischemic necrosis are visualized on MRI. Multiorgan dysfunction may progress in well oxygenated neonates. The authors’ eligibility criterion of the five-minute Apgar <5 also conflicts with the diving reflex model. At five minutes, all children had ventilated lungs. With a maximum Apgar of 4, it is difficult to conceive that any were pink; the diving reflex model would be pink. Pulmonary dysfunction at five minutes indicates inadequate pulmonary perfusion and possibly failure to convert from fetal to adult circulation – a process in which placental transfusion plays an integral part; [7] hypoxia is not a factor. Most, if not all neonates in this study had the placenta amputated at the moment of birth together with a large volume of blood. That placental blood volume normally initiates function in the child’s life support organs; the hypovolemic / ischemic nature of MOD is thus explained, and the diving reflex (hypoxic) explanation discredited. The only effective treatment of hypovolemia is restoration of blood volume, ideally with whole blood. This is readily accomplished in post asphyxial neonates by resuscitating them with the placental circulation intact. A 50+% increase in blood volume using oxygenated, non-acidotic blood from the placenta will usually result in a five-minute Apgar score of 10, will prevent ischemic injury and will activate normal function in multiple organs, especially the brain. Note: In August 2003, ACOG withdrew Practice Bulletin 138 from publication. Immediate amputation of a functioning placenta is no longer an officially recommended procedure in the US. The prudent obstetrician should approach a pulsating cord with due caution. If the child is not pink and breathing, there is no indication to destroy the child’s only functioning life support system. References 1. Cashmore J. Usher RH. Hypovolemia resulting from a tight nuchal cord at birth. Pediatr. Res 1973;7:339. 2. Gunther M. The transfer of blood between the baby and the placenta in the minutes after birth. Lancet 1957;I:1277-1280. 3. Usher, R. Shephard M,Lind J. Blood Volume in the Newborn Infant and Placental transfusion. Acta Paediatrica 1963; 52: 497-512 4. Arcilla RA, Oh W. Lind J. et al. Portal and atrial pressures in the newborn period. Acta Paediatr. Scand. 1966;55: 615-625 5. Linderkamp O. Placental transfusion: determinants and effects. Clinics in Perinatology 1982;9:559-592 6. Peltonen T. Placental Transfusion, Advantage - Disadvantage. Eur J Pediatr. 1981;137:141-146 7. Jaykka S. Capillary Erection and Lung Expansion. Acta Paediatr. 1965 [nppl] 109.
Retraction Respiration: the Multiorgan Dysfunction that Causes Ischemic Encephalopathy 21 May 2004
George M. Morley, Retired obstetrician-gynecologist none, none Send letter to journal: Re: Retraction Respiration: the Multiorgan Dysfunction that Causes Ischemic Encephalopathy obgmmorley{at}aol.com George M. Morley, et al.	Dear Editor Retraction respiration (RR) is a pulmonary dysfunction frequently seen in neonates that develop hypoxic-ischemic encephalopathy. (HIE) It consists of short, strong inspiratory efforts using accessory muscles such as the sterno-mastoid to elevate and expand the rib cage that result in retraction of the sub-costal abdominal wall and intercostal skin. Clinically it is gasping respiration. RR is a reflexive reaction to hypo-volemia, hypotension and low venous return to the heart. It generates pulses of negative intra- thoracic pressure (NIP) that pull blood into the heart and increase venous return. Gasping (RR) is well illustrated in Meyers’ research on primate neonatal brain damage caused by asphyxia. [1] In Shah’s investigation [2] of the relationship of multiorgan dysfunction to outcome in post-asphyxial HIE, pulmonary dysfunction is defined as “need for ventilator support with oxygen requirement > 40% for at least the first four hours after birth.” It is the most likely organ dysfunction to be associated with HIE – 86% regardless of outcome; however, Shah’s definition of HIE did not include MRI evidence of ischemia, and 50 out of 130 infants with clinical “HIE” had “good outcomes.” Therefore this clinical definition consists of 38% of neonates with impaired, but fully recoverable, cerebral function, and 62% with neuron necrosis and permanent brain damage. Correction of asphyxia does not affect outcome; it would appear that something other than asphyxia damages the brain. Shah’s criteria for renal and cardiovascular dysfunction imply hypovolemic and severe hypotensive origins for these dysfunctions. Outcome in both cases trends to the adverse, indicating hypotension as a factor in brain damage. RR lowers alveolar pressure and predisposes to pulmonary edema – crepitations; thus it is a significant factor in “the need for ventilator support” and positive alveolar pressure ventilation. However, RR also occurs in “HIE” neonates that do not meet Shah’s criteria for pulmonary dysfunction. If during strong “gasps,” the NIP exceeds the neonatal blood pressure, reverse flow in the carotid and vertebral arteries may drain blood from the brain and be a major cause of brain ischemia. Meyers’ recordings of heart rate, blood pressure and gasping confirm this scenario. [1] In Figure 1, [1] the cord was clamped immediately after birth and a rubber bag placed over the monkey neonate’s head, preventing breathing. The heart rate drop from 160 to below 100 signifies immediate hypoxia / anoxia and loss of placental blood return to the heart. The following decline in blood pressure signifies gradual anoxic heart failure over a period of ten minutes. Brain perfusion ceases with zero blood pressure and neuron necrosis begins. When the BP falls below 50 mms Hg, gasping (RR) starts; gasping later recurred with hypotension during resuscitation (oxygenation). The stimulus for gasping may be either low systemic blood pressure or deficient atrial filling – low central venous pressure. In either case, the effect of gasping is to create NIP that pulls blood into the heart and lungs. The gasps produce dramatic spikes of increase in the heart rate, and similar spiking decreases in the diastolic blood pressure to the zero line. NIP counteracts the left ventricle (BP) during a gasp; if they are equal, no blood leaves the thorax. If blood pressure is low and the gasp strong, blood may flow backwards through the carotid and vertebral arteries (and abdominal aorta) into the intra thoracic aorta. Thus a strong gasp during severe hypotension may cause a NEGATIVE diastolic blood pressure that is recorded as zero; it may entail temporary venous AND ARTERIAL blood drainage from the brain. In Figure 1, [1] negative diastolic readings may have occurred for a period of five minutes followed by a period of zero blood pressure. This monkey had severe brain damage. Transposing the above scenario to the immediately cord clamped (ICC) human neonate (no placental transfusion) that has a large portion of its blood volume left in the placenta, ventilation fills the pulmonary circulation with blood, leaving the systemic circulation hypovolemic. Depending on the degree of hypovolemia, the blood pressure, central venous pressure and cardiac output all fall; the neonate responds with retraction respiration. A similar situation appears during resuscitation in figure 1 [1] with spikes of low BP during gasps. The net effect of retraction respiration is that thoracic organs are filled with blood and an adequate pulmonary circulation is established at the expense of the systemic circulation. In the extreme, blood in the carotid and vertebral arteries may be well oxygenated, but with gasping combined with hypotension, flow in these vessels may be tidal, with very little blood flowing through brain capillaries at the height of left ventricular systole. Such episodes that last for more than five minutes could account for the development of HIE. The areas of the brain that are most metabolically active– the basal ganglia and the cerebral cortex – are the first to necrose from loss of nutrients. Confirmation of the above phenomenon should be readily available by Doppler observation of blood flow in the carotid arteries of any child with retraction respiration. Retraction respiration is avoidable by not clamping the cord and resuscitating with the placental circulation intact – placental transfusion supplies the required adequate blood volume. This is illustrated in figure 16. [1] The fetus was asphyxiated by maternal anoxia. In contrast to figure 1, asphyxia produces a much smaller decrease in blood pressure when placental blood volume is not removed, and cord clamping after ventilation (and after placental transfusion) results in increases in pulse rate and blood pressure. This newborn monkey in figure 16 was normal. In the retracting neonate that has suffered immediate cord clamping, immediate intravenous administration of a blood volume expander such as Plasmanate with monitoring of central venous pressure and metered blood volume replacement should also prevent brain damage. Administration of an inotrope for treatment of hypotension should be withheld until central venous pressure is adequately positive with blood volume replacement; usually inotropes will not be needed. Conclusion Meyers [1] concluded that asphyxia / hypoxia injured the primate brain. The brain lesions that he and Windle [3] produced in Rhesus monkeys duplicate very closely those recorded in human HIE neonates that suffered from intra-partum asphyxia; however, the degree of asphyxia in the human HIE neonate is minor compared to that required to damage a monkey’s brain. Review of Meyers’ records, in conjunction with modern studies such as Shah’s, [2] place hypo-perfusion, not hypoxia as the cause of neuron necrosis. In the monkey, hypoxia produces heart failure and hypotension; in the human, hypovolemia (from ICC) produces the hypotension. In both cases, RR confirms the presence of severe hypotension that drains blood from the brain. Retraction respiration in a neonate is an absolute indication that the child is hypovolemic and hypotensive; prompt correction of the hypovolemia and the hypotension by blood volume replacement is essential for maintaining the integrity of the brain. Brain damage in HIE is produced by inadequate perfusion of brain tissue with blood. Blood pressure is the force that maintains adequate perfusion of brain tissue. In the neonate that has been subjected to immediate cord clamping, hypotension, and RR (gasping) may generate enough negative intra-thoracic pressure to force arterial blood to flow into the thorax and out of the brain, thus accelerating the onset of ischemic neuron necrosis in HIE. To avoid HIE and CP, resuscitation of all neonates should be done with the placental circulation intact, allowing the cord pulsation to cease before clamping the umbilical cord. Myers’ Figure 1 [1] and Figure 16 [1] may be viewed online at: http://cordclamping.com/bmjRetrRespletter.htm References 1. Myers RE (1972) Two patterns of perinatal brain damage and their conditions of occurrence. American Journal of Obstetrics and Gynecology 112:246-276.30. 2. Shah, P. Riphogen, J, Beyene, J, Perlaman, M. Multiorgan Dysfunction in Infants with Post-asphyxial Hypoxic Ischaemic Encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004;89;F152-155. doi: 10.1136/adc.2002.023093 3. Windle W. Brain Damage by Asphyxia at Birth. Scientific American. 1969 Oct;221(4):76-84.
Reply to Tarcan et al. 30 June 2004
Prakesh S Shah, Neonatologist Department of Paediatrics, Mount Sinai Hospital, University of Toronto, Canada, Max Perlman Send letter to journal: Re: Reply to Tarcan et al. pshah{at}mtsinai.on.ca Prakesh S Shah, et al.	Dear Editor We read with interest the letter by Tarcan et al. [1] in response to our article.[2] Tarcan et al. [1] discussed specifically the criteria for the hepatic involvement in post-asphyxial hypoxic ischemic encephalopathy (PA-HIE) infants. We agree with Tarcan et al.[1] that ALT is a better marker of liver injury than AST for the reasons given in their letter. To compare our results with those of Tarcan et al., we re-analysed our data, based on ALT alone. AST > 100 Units was observed in 116/128 (91%) of patients who were tested, whereas ALT exceeded 100 Units in 61/126 (48%). Thus, based on the ALT criterion the incidence of hepatic involvement was closer to the 33% reported by Tarcan et al. in their letter. However, in terms of differences in the long-term outcome, no significant differences based on either were detected (Table 1). We will be interested to compare our subjects with those of Tarcan et al,[1] with respect to demographic details and measures of the severity of illness such as outcomes. In comparing our results with those of Tarcan et al,[1] we also calculated and compared the highest levels of AST in babies with ALT >100 and those with levels <100. The mean + SD value for AST in the high ALT group was 750 + 704, and in the low ALT group was 196 + 110 (Mann Whitney test, p <0.0001). The difference between our results and those of Tarcan et al. [1] for this observation may be attributable to differences in the statistical power. We would like to make two suggestions regarding the use of ALT and AST. First, although the values of 100U/L or lower has now been used for both AST and ALT by other authors including ourselves,[1-4] this is questionable owing to the higher levels of AST compare to ALT in both normal and asphyxiated neonatal subjects. This criterion is arbitrary. Secondly although AST is less specific than ALT for liver dysfunction, it may have a role as a criterion for multi organ dysfunction, because its sources are outside the brain. We are pleased to note that Tarcan et al. [1] agree with our assertion that consensus is needed regarding the criteria for dysfunction of individual organs/systems during the first hours and days in the postnatal period. We hope that this correspondence will contribute to that end by stimulating further discussion as well as research. Table 1 Combinations of ALT and AST values and their relation to outcome Combination of ALT and AST Outcome Total Good N (%) Adverse N (%) ALT>100 & AST>100 20 (38%) 33 (62%) 53 ALT<100 & AST>100 19 (48%) 21 (52%) 40 ALT>100 & AST<100 0 (0%) 2 (100%) 2 ALT<100 & AST<100 0 (0%) 6 (100%) 6 ALT>100 & AST not tested 0 (0%) 1 (100%) 1 AST>100 & ALT not tested 5 (36%) 9 (64%) 14 ALT<100 & AST not tested 6 (50%) 6 (50%) 12 AST<100 & ALT not tested 0 (0%) 2 (100%) 2 Total 50 (38%) 80 (62%) 130 Chi Square = 8.99, df =7, p=0.259 References (1) Tarcan A, Grakan B, Tiker F. Questioning the Criteria for Hepatic Involvement In Hypoxic-Ischemic Encephalopathy [electronic response to Shah et al. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy ] archidischild.com 2004 http://fn.bmjjournals.com/cgi/eletters/89/2/F152#361 (2) Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004; 89(2):F152-F155. (3) Hankins GD, Koen S, Gei AF, Lopez SM, Van Hook JW, Anderson GD. Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. Obstet Gynecol 2002; 99:688-91. (4) Phelan JP, Ahn MO, Korst L, Martin GI, Wang YM. Intrapartum fetal asphyxial brain injury with absent multiorgan system dysfunction. J Matern Fetal Med 1998;7:19-22.
Reply to Morley 15 September 2004
Prakesh S Shah, Staff Neonatologist and Assistant professor Mount Sinai Hospital and University of Toronto, Max Perlman Send letter to journal: Re: Reply to Morley pshah{at}mtsinai.on.ca Prakesh S Shah, et al.	Dear Editor, We are glad to respond to the comments of Dr. George Morley [1] on our paper entitled “Multiorgan Dysfunction in Infants with Post- asphyxial Hypoxic Ischaemic Encephalopathy”.[2] Dr. Morley raised the possibility that the cause of the HIE in our patients was hypovolaemia due to deprivation of the placental transfusion (with or without tight nuchal cord) rather than intrapartum asphyxia. We will attempt to respond to most of the items in Dr. Morley’s two letters. First, we wish to define “asphyxia”. Asphyxia is defined in the literature on either a pathophysiological or syndromal basis. The former consists of hypoxia, hypercapnia and metabolic acidaemia. The latter is defined in various consensus statements of national obstetrical and other professional societies, and in the so-called International Consensus Statement. [3] It is our strong impression that noone today accepts depression at birth or, for example a low 5-minute Apgar score as a definition of asphyxia. We wish to point out that Dr. Morley’s statement regarding the 5-minute Apgar score is not relevant to our study, as a score of <5 was not an essential inclusion criterion; it was one of three sub-criteria. In our response to Dr. Morley, the unqualified term “asphyxia” indicates either pathophysiological or syndromal asphyxia, “severe” asphyxia means both pathophysiological and syndromal asphyxia, and mild or mild to moderate asphyxia implies pathophysiological asphyxia only. In his letter, Dr. Morley questions the plausibility of the diving reflex as a response to asphyxia. Knowledge of the fetal and neonatal diving reflex is based mainly on experiments in animals, and on clinical observations in the human newborn infant (we compare the two in more detail below). For animal data on the diving reflex in severe asphyxia, the interested reader is referred to the paper of Behrman et al3, and a detailed recent review by Jensen et al on fetal circulatory responses to hypoxia and asphyxia induced by various means.4 A considerable body of evidence suggests that in the human with hypoxia and asphyxia, the circulation is centralized to brain, heart and adrenal gland (the so-called “vital organs”).[2,4] Dr. Morley reiterated some of our criteria for organ involvement and pointed to some differences; owing to limitations of time we will not deal with our relatively minor differences of opinion. Dr. Morley points out that the diving reflex “does not last very long”. At some point in the progression of severe asphyxia in animals, the reflex breaks down. [4] When the diving reflex breaks down, the non-vital organs are likely to be more acidotic than the vital organs, so the latter have a relative advantage. It is reasonable to think that during the period that the reflex is active and for some period after, this compensatory mechanism provides relative protection to the vital organs. Dr. Morley relates to repeated cord compression, the diving reflex and organ damage/ dysfunction. Before addressing this issue, we wish to point out that in contrast to “dysfunction”, organs other than brain and heart rarely sustain irreversible damage in severe asphyxia. We therefore prefer to use the term “dysfunction” to “damage”. In animal models, repeated hypoxic episodes with intervening episodes of recovery or partial recovery (the prolonged partial asphyxial model of Myers[5]) was more strongly associated with multi-organ dysfunction than continued severe asphyxia with prolonged bradycardia (the “total” asphyxia animal model of Windle[6]).[4] Analogies have been drawn to human conditions,[7,8] but to our knowledge, no empirical evidence has been published that compares the multi-organ dysfunction after acute near- total vs. prolonged partial insults. To clarify this issue, we reviewed and analyzed our data. Since all of our patients with post-asphyxial hypoxic ischemic encephalopathy (HIE) had multiorgan dysfunction (MOD), the subgroups defined by the above time-courses of asphyxial insult were identical regarding the presence of MOD. We also determined from our data the proportion of infants with two or more dysfunctional organs in the two groups. Of infants in the acute near-total group, 70 percent had two or more dysfunctional organs, whereas 80 percent of infants in the prolonged partial asphyxia group had two or more dysfunctional organs. This difference was not statistically significant, nor do we consider it clinically significant. Dr. Morley points to hypovolaemia as a pathophysiological mechanism that may supplement the adverse effects of co-existing asphyxia. He refers to two causes of hypovolaemia: cord compression as a cause of acute fetal blood loss into the placenta, and early clamping of the umbilical cord by depriving the newborn infant of the placental transfusion. We are glad that Dr. Morley draws attention to these phenomena; it is our impression that both are under-recognized as potential contributing causes of brain injury, especially when co-existing with asphyxia. Nuchal cord, especially if tight, results in blood loss due to compression of the umbilical vein but not the arteries, as well as asphyxia due to failure of placental gas exchange, either or both varying from none to severe.[4,5] Haemorrhagic shock representing a threat to the brain occurs only in extreme cases. [6] In our study, we excluded infants with haemorrhagic shock. Infants thought to have “pure” haemorrhagic shock, which presents with relatively mild depression at birth and a progressive postnatal depression until blood volume is replenished, were excluded. Babies with tight nuchal cord and haemoglobin concentrations within normal limits were considered to have suffered “pure” asphyxia and were included in the study. The mean haemoglobin and haematocrits of our patients (including those with tight nuchal cord) were 161 g/l and 0.47, higher than the mean values for infants with tight nuchal cord studied by Cashore and Usher [4] (haematocrit 0.39), and similar to the values observed by Shepherd et al5 (mean haematocrit 0.48 and haemoglobin 164 g/L), and Linderkamp et al7 (haematocrit 0.46). It is notable that the infants studied by Cashore and Usher [4] (with an average blood loss of 20 percent of blood volume) showed only pallor and mild hypotension in the hours after birth; post-asphyxial HIE was not reported. Of the 27 cases of Shepherd et al5 with tight nuchal cord eligible for their study, [5] had haemoglobin values less than 132 g/L (which we consider to be well below the lower limit of normal) and [3] received emergency blood transfusion for pallor, tachycardia and hypotension. These authors also did not report HIE in their subjects. In our experience term infants can tolerate acute blood losses of up to 40 percent of blood volume and even more without developing obvious haemorrhagic shock, provided that they are free of preceding or concurrent asphyxia. Early clamping of the umbilical cord with deprivation of the placental transfusion is also a well established cause of peri-partum hypovolaemia. Many published studies have compared early with delayed timing of cord clamping of apparently healthy infants born after uncomplicated pregnancy and parturition or Caesarean section. A number of studies of preterm infants have also been performed. In many studies, early clamping was accomplished within seconds of birth. Delayed clamping was defined in most studies as three minutes after birth or by cessation of cord pulsation. The effects of “delayed” and “early” cord clamping have been compared for a great variety of end-points including haematological, respiratory, cardiovascular, rheological and renal function measurements. Early clamping undoubtedly leaves some infants “with an uncomfortably small blood volume”.8 On the other hand, late clamping is associated with more jaundice [9] and hyperviscosity. [10] To our knowledge, a comprehensive health outcome has not been studied in relation to placental transfusion. Studies of the effects of timing of cord clamping in severely asphyxiated infants and experimental animals have provided mixed results. According to Smith [11] “perinatal asphyxia may speed and increase the process of placental transfusion, even unto a prenatal transfusion.”[11] Hey [8] stated that “fatally asphyxiated babies usually have a relatively high haematocrit and circulating blood volume at birth.” The studies of Ackerman and colleagues [12,13] showed that infants with low Apgar scores and low umbilical arterial pH at birth tended to have small residual placental blood volumes, suggesting that a shift of blood volume from placenta to foetus had preceded cord clamping. These observations accord with those of Behrman et al in the experimental fetal primate. [14] By contrast, acute intrapartum asphyxia defined as a 1- minute Apgar score of 5 or less was found to be associated with a reduced haematocrit of 0.49 (cord clamped at 15 seconds) as compared with 0.54 in infants with scores of 6 or greater (both were delivered vaginally). [7] This was considered to be caused by a shift of blood from fetus to placenta. In view of the early cord clamping at 15 seconds, another interpretation of this finding is possible. The infants with low 1-minute Apgar scores may represent the infants to which Dr. Morley refers. The depressed 1-minute Apgar scores and lower haematocrits may be attributable to early clamping of the cord and deprivation of a relatively large portion of the placental transfusion in some infants. As with the instances cited above from the literature, no mention is made of HIE in the 17 term infants studied. In addition, the definition of “acute intrapartum asphyxia” would not be acceptable on either pathophysiological or syndromal grounds. The appropriate time to clamp the cord of babies with severe asphyxia has, to our knowledge, not been the subject of clinical trial. In a review of placental transfusion, Yao and Lind [15] stated: “In the presence of foetal distress or birth asphyxia, even during a vaginal delivery, it is also advisable not to delay clamping of the cord to avoid hypovolaemia except when there is obvious evidence of fetoplacental bleeding before and during birth and the infant appears pale and in shock. In such circumstances, cord clamping should be delayed if resuscitation can be given simultaneously. Otherwise, early separation of the infant from the cord will facilitate the resuscitation.” Non-response to initial resuscitation measures suggests the possibility of hypovolaemia and the need for blood volume expansion. During placement of the umbilical venous catheter, central venous pressure can be measured; a low pressure is an additional indication for emergency blood volume expansion. Blood volume expansion is initially provided by colloid or crystalloid, soon followed by blood if indicated. [16] Group O rhesus negative whole blood should be given with great urgency if there is historical or physical evidence of a large acute blood loss (e.g., velamentous insertion of the cord with a tear in a large blood vessel; incision of the placenta prior to the delivery of the infant during the Caesarean section) and if the infant has signs of haemorrhagic shock (extreme pallor, weak peripheral pulses, hypotension, etc.). The appropriate time to clamp the cord in an intermediate group of infants born after complicated deliveries with relatively mild depression has also not been the subject of clinical trial. We have seen babies born with mild to moderate asphyxia associated with tight nuchal cord, whose condition deteriorated after birth until the hypovolaemia was corrected, and who proved to be moderately severely anaemic. The severity of the anaemia caused by deprivation of blood volume in some cases of tight nuchal cord is far greater than the physiological placental transfusion would have been. A similar effect can be caused by gravity (holding the newly born infant well above the level of the placenta before clamping the cord).[17] Another potential cause of neonatal blood loss is the removal of cord blood for banking for possible future autologous cord blood transplantation (blood volumes as large as 110 ml, or about one- third of a 4 kg birth weight infant, have been banked). Hypovolaemia associated with mild to moderate intrapartum asphyxia, if not speedily recognised and treated by blood volume expansion, may cause neonatal morbidity. We did not find the statement attributed by Dr. Morley to Peltonen18 that “In the compromised neonate, immediate cord clamping may result in fatality” was not found on review of the cited article. Peltonen [18] did allude to the “highly unphysiological” effects of early clamping on the neonatal heart during the first three or four cardiac cycles after cord clamping and before the first breath. He also referred to the animal study of Born et al [19] in which clamping of the cord before the onset of pulmonary respiration caused “profound asphyxia”. Despite these observations, Peltonen [18] concluded his review of early cord clamping with the citation that “It appears that umbilical cord clamping should be done at the discretion of the obstetrician.” To our knowledge no studies have been conducted that compared measures of neonatal well being including morbidity and mortality in early-clamped with late-clamped term infants born after uncomplicated deliveries. This is not surprising in light of the large sample size that would be required for such a trial, and ethical hesitations about depriving some infants of large blood volumes, and causing polycythemia in others. In light of the observed adverse associations with very early and with delayed clamping, avoiding these extremes would appear to be sensible. Likewise, delay in resuscitation of a severely asphyxiated infant to await a placental transfusion that is unlikely to occur owing to constricted umbilical arteries is likely to cause more harm than benefit. One circumstance that may justify an attempt to resuscitate the term infant with an intact foetal circulation may be after delivery complicated by tight nuchal cord in which it proved possible to deliver the infant without ligating and cutting the cord. Even in this situation, one can speculate that delay in clamping the cord may be harmful. For example, re-establishing the umbilical-foetal placental circulation after a period of stasis may cause placental thromboembolism and consequent harm such as neonatal stroke. Randomized controlled trials comparing different timings of placental transfusion may be justified for some populations. One example referred to above is mild to moderate asphyxia where it is likely that the infant is in primary rather than secondary apnoea. Another is the newly born small for gestational age infants (presumably the “intra-uterine asphyxia” or placental insufficiency group of Linderkamp [7]). On the other hand, in our opinion it would be far more difficult to persuade a research ethics committee today to approve a comparative trial of delayed clamping (with attendant suboptimal conditions for resuscitation) versus immediate clamping (to optimize the resuscitation conditions) in severely asphyxiated infants who are most likely in secondary apnoea. Likewise, it would be difficult to justify a comparison of measures of neonatal well being, morbidity and mortality in very early-clamped with very late- clamped apparently healthy term infants, especially as so much is known about the effects of deprivation or maximization of placental transfusion in these infants. Whatever happens to the depressed infant at birth with regard to cord-clamping, the team progressing through the steps of resuscitation should not overlook the possibility that blood volume expansion may urgently be indicated. With regard to sampling of blood gases Dr. Morley refers to the “later withdrawn” ACOG Practice Bulletin 138 which suggested that obstetricians clamp the cord quickly in order to send samples for blood gases. In the process they “amputate a functioning placenta”. He advises “the prudent obstetrician” to “approach the pulsating cord with due caution”. We agree with this advice with emphasis on “a pulsating cord”. Parenthetically, repeated research has indicated that delayed cord clamping is advantageous for the adaptation of the preterm infant to extra-uterine life.[20,21] The reason often given in the past for early clamping of preterm infants was the perceived threat of the increased levels of jaundice associated with late clamping in the pre-phototherapy era. This is of much less concern today than it was when phototherapy was unavailable and before it was found to be efficacious and safe. Late clamping of preterm infants is probably safer than early clamping. We agree that for the infants who are more likely than not to benefit from delayed cord clamping, the technical difficulty that may be caused by the delay in sampling from the cord artery may be relatively unimportant, and the potential enhancement of the circulating blood volume is the greater priority. To complete the diagnosis (pathophysiological or syndromal) of asphyxia, and if necessary its treatment, a sample can be taken from the infant rather than the cord. This has the advantage of avoiding errors such as sampling from the umbilical vein instead of an artery. Moreover, even umbilical arterial samples after severe cord compression are occasionally unrepresentative of the infant’s condition at birth, and capillary sampling is likely to reflect the infant’s current condition more accurately. Dr. Morley also addressed the issue of hypoxic versus ischemic aetiopathogenesis of brain lesions. Considerable ambiguity exists between the terms “hypoxia” and “ischaemia”. From the aetiological standpoint (aetiology meaning “root cause”) we interpret Dr. Morley’s statements to differentiate between the hypoxia of asphyxia, and the ischaemia of hypovolaemia (in the context of his letter, hypovolaemia is caused by acute blood loss due to deprivation of the placental transfusion, associated or not with early cord clamping or tight nuchal cord). From the aetiological standpoint, we prefer the term “haemorrhagic shock” to describe the latter condition. Haemorrhagic shock causes tissue hypoxia, the end-results of which on brain and other organs are very similar to those of severe asphyxia (incidentally, one intermediate result that asphyxia and hypovolaemic shock have in common is the centralization of the blood circulation). On the other hand, severe asphyxia is often associated with hypotension, the pathogenesis (mechanism as opposed to aetiology) of which is vasodilatation. Whatever the pathogenesis of ischaemia in severely asphyxiated infants (eg, cerebral vasoconstriction due to break-down in the protective diving reflex, cardiogenic shock, or hypovolaemic shock of the various causes considered above), it is considered to be the more important pathogenetic mechanism of brain injury than the hypoxia that is an essential part of the definition of asphyxia (with mild to moderate asphyxia, the fetus is unlikely to develop ischaemia and to sustain brain injury). The complexity of these overlapping conditions is nicely illustrated by the example of extreme cases of tight nuchal cord in which severe asphyxia and haemorrhagic shock coexist. To our knowledge brain MRI cannot differentiate between the end-results of severe asphyxia with secondary brain ischaemia, and haemorrhagic shock. As indicated above, we wish to compare the primate fetus with severe asphyxia studied mainly between the 1960s and the 1970s as a model for brain injuries associated with severe fetal asphyxia in the human. Dr. Morley’s statement that “the degree of asphyxia in the human HIE neonate is minor compared to that required to damage a monkey’s brain” is surprising. The relative immaturity of the term human fetus and the larger stores of glycogen compared with the monkey fetus would be expected to provide the human with greater tolerance to severe asphyxia. This appears to be supported by empirical data. Perusal of recently published case series that report durations of sustained bradycardia and outcomes in a variety of near-total asphyxia scenarios shows that the human fetus with sustained bradycardia seems to have greater staying power than the experimental fetal term monkey with total asphyxia and sustained bradycardia. For example, in a report of the short-term outcomes of the babies of 97 women with uterine rupture (82 of whom had a trial of labour); it was observed that “significant neonatal morbidity” occurred only in those cases in which “18 or more minutes elapsed between the onset of the prolonged deceleration and delivery”. This was the case even in cases that had prior severe late or variable decelerations. Of the 13 babies with sustained decelerations for 18 or more minutes without prior severe late or variable decelerations, only one (with 32 minutes of deceleration) had a severe neonatal outcome, viz, HIE (the long-term outcome was not reported). [22] Review of published case series of severe total or near-total asphyxia provides a similar perspective. For example, Cases 3 and 4 of Pasternak and Gorey [23] had uterine rupture and known durations of bradycardia (18 and 15 minutes); their outcomes were relatively moderate (respectively, mild spasticity and dystonia with normal cognition and head circumference at 3.5 years of age, and mild transient hypotonia and normal cognition and head circumference at 4 years of age). Of particular interest is Case 9 with umbilical cord rupture (an acute total asphyxia; blood loss was not mentioned); sustained bradycardia was present for 31 minutes; this infant had mild transient hypotonia with normal cognition and head circumference at 18 months. [23] These durations of bradycardia are beyond the duration of bradycardia seen in experimental total asphyxia that proved lethal in term rhesus monkeys. We summarize by stating where we agree and disagree with Dr. Morley. We disagree that “Most, if not all neonates in this study had the placenta amputated at the moment of birth together with a large volume of blood.” In our opinion, it is likely that the umbilical cord had lost its function in the great majority of our cases by the time the cord was clamped; these were cases of severe asphyxia. In our opinion, maintaining the umbilical cord connection was unlikely to provide a placental transfusion. “Amputation” of a non-functioning placenta with poor potential for recovery of function is appropriate. Based on the eligibility and exclusion criteria of our study, and on the haemoglobin and haematocrit values reported here, we are confident that immediate cord clamping did not cause significant blood losses in the great majority of our cases. On the other hand we emphasize that we agree with Dr. Morley that early clamping of the pulsating cord of an infant may cause harmful blood losses and postnatal haemorrhagic shock, particularly in infants who were mildly to moderately asphyxiated at birth with a shift of blood volume from fetus to placenta. Similarly, placement of an infant above the level of the placenta without clamping the still-functioning cord, or “transplanting” cord blood in large volume may cause harmful blood losses. Dr. Morley has drawn attention to aspects of neonatal care that are sometimes overlooked in contemporary practice. We hope that this correspondence will stimulate clinicians to review the older literature on placental transfusion, cord clamping, and haemorrhagic shock. Where questions still remain to be answered, there is a place for new clinical and even animal studies to elucidate the role of sequestration of blood in the placenta in the aetiopathogenesis of maladaptation at birth, and of neonatal brain illness and injury. References (1). Morley GM. Hypovolemia:The Cause of Multiorgan Dysfunction. 2004. BMJ Publishing Group. http://fn.bmjjournals.com/cgi/eletters/89/2/F152#407 (2). Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 2004;89:F152-F155. (3). MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054-9. (4). Cashore WJ, Usher RH. Hypovolemia resulting from tight nuchal cord at birth. Pediatr Res 1973;7:339. (5). Shepherd AJ, Richardson J, Brown JP. Nuchal cord as a cause of neonatal anemia. Am J Dis Child 1985;139:71-3. (6). Vanhaesebrouck P, Vanneste K, De Praeter C, Van Trappen Y, Thery M. Tight nuchal cord and hypovolaemic shock. Arch Dis Child 1987;62:62-3. (7). Linderkamp O, Versmold HT, Messow-Zahn K, Muller-Holve W, Riegel KP, Betke K. The effect of intra-partum and intra-uterine asphyxia on placental transfusion in premature and full-term infants. Eur J Pediatr 1978;127:91-9. (8). Hey E. Resuscitation at birth. Br J Anaesth 1977;49:25- 33. (9). Saigal S, O'Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and hyperbilirubinemia in the premature. Pediatrics 1972;49:406-19. (10). Linderkamp O, Nelle M, Kraus M, Zilow EP. The effect of early and late cord-clamping on blood viscosity and other hemorheological parameters in full-term neonates. Acta Paediatr 1992;81:745-50. (11). Smith CA, Nelson NM. The physiology of newborn infant. In: Thomas CC, 4th ed. 1976:157-77. (12). Chou PJ, Ackerman BD. Perinatal acidosis and placental transfusion. Acta Paediatr Scand 1973;62:417-21. (13). Flod NE, Ackerman BD. Perinatal asphyxia and residual placental blood volume. Acta Paediatr Scand 1971;60:433-6.
Response to Prof. Shah's Letter 4 November 2004
George M. Morley, Retired Obstetrician None Send letter to journal: Re: Response to Prof. Shah's Letter obgmmorley{at}aol.com George M. Morley	Dear Editor, Professor Shah has submitted a comprehensive and well-documented response that agrees and disagrees with my letters. With clarification of a few points, I find that we may be very close to complete agreement, and to major improvement in neonatal outcome. Regarding the definition of “asphyxia,” for want of a better, I use the term to describe the sum total of pathologies produced by compression of the umbilical cord. This may not fit the definition of “the so-called International Consensus Statement”, but it focuses elucidation onto the single, most common cause of fetal/neonatal “asphyxia,” namely, cord compression. It also eliminates confusion with pathologies generated by other causes of birth “asphyxia” such as placental abruption and meconium aspiration. Professor Shah cites many papers on birth asphyxia/acidosis that have apparent contradictions regarding placental blood volume, placental transfusion and cord compression, pH, hemoglobin and hematocrit readings. He correctly defines “infants to which Dr. Morley refers” as acute intrapartum asphyxia (cord compression) plus immediate cord clamping (ICC) resulting in neonatal hypovolemia These fetuses have large blood volume shifts TO the placenta just prior to delivery, and the phenomenon was described by Linderkamp [1] as “intrapartum asphyxia.” Linderkamp also differentiates “intrauterine asphyxia” (prior to labor, or in early labor) that causes a marked shift of blood volume from the placenta. These peculiar reverse effects of “asphyxia” and most of the conflicting reference studies are readily explained on the degree and chronicity of the cord compression “asphyxia”. Cord venous compression engorges the placenta, raises placental intra -capillary hydrostatic pressure and thus forces fluid into the mother, dehydrating the fetus. If the cord compression is not intermittently relieved, as in oligohydramnios where the cord has no fluid buffer between fetal parts and the uterine wall, fetal dehydration and hemoconcentration may become extreme; hypovolemia with very high hematocrit values results. The fetus responds to hypovolemia / dehydration with generalized vasoconstriction that ,i>includes placental and cord vessels. Such babies are born limp and ashen white, covered in “pea soup” meconium and the cord often appears white with three “pencil streaks” of vessels. Placental transfusion has already occurred and little placental function is available; the correct treatment is immediate cord clamping followed by immediate intravenous correction of the dehydration, acidosis and electrolyte imbalance with pulmonary resuscitation. [2] This is Linderkamp’s “intrauterine asphyxia.” I completely concur with Professor Shah’s statement that: “Likewise, delay in resuscitation of a severely asphyxiated infant to await a placental transfusion that is unlikely to occur owing to constricted umbilical arteries is likely to cause more harm than benefit.” With acute intrapartum cord compression with intermittent relief, (late decelerations) dehydration is a very variable factor, but a significant one in the more severe cases. By relieving the cord compression at birth (releasing a tight nuchal cord on delivery of the head) and permitting third stage placental circulation to continue, placental oxygenation, placental correction of acidemia and placental re- hydration with restoration of electrolyte balance rapidly restore the physiological state while the neonatal blood volume is adjusted by placental transfusion. The mandatory clinical factor in this procedure is a vigorously pulsating cord; a factor that Professor Shah agrees should not be destroyed. This is Linderkamp’s “intrapartum asphyxia.” However, if the intrapartum cord compression has been more chronic, without much intermittent relief, more severe dehydration and placental / cord vasoconstriction may have shifted blood volume to the fetus, and the birth condition approaches that of “intrauterine asphyxia.” Management depends on the condition of the cord vessels at birth. If they are constricted, placental function is marginal and immediate clamping and I.V. hydration with resuscitation is the choice. If there is active cord pulsation above 100 b.p.m. and the vein is filled, placental function should be used to correct hypoxia, acidemia, dehydration, electrolyte imbalance and hypovolemia while ventilation is being established. In severely acidotic, hypoxic neonates (cord arterial blood values) the cord venous blood is usually well oxygenated with a normal pH. With release of cord compression at birth, circulation through the massive placental / maternal interface will rapidly correct the pathologies created by cord compression and with much greater accuracy and efficiency than procedures done after immediate amputation of the placenta. In the case of preterm infants, it is very encouraging to find a neonatologist stating: “Late clamping of preterm infants is probably safer than early clamping.” and in regard to umbilical cord blood sampling: “If necessary its treatment, a sample can be taken from the infant rather than the cord.” The following critique of blood loss and blood transfusion is from an obstetrician’s perspective and does not concur with current Neonatolgy philosophy. Obstetrical blood loss (maternal hemorrhage) is rapid and often massive. Obstetrical management is rapid and massive. The adequacy of residual blood volume after blood loss is measured in terms of blood pressure, pulse rate, central venous pressure and urine output; hemoglobin and hematocrit values (unless extreme) are irrelevant. Acute blood loss mandates rapid blood volume replacement to avoid hypovolemic sequelae. Whole blood is the best replacement; otherwise plasma volume expanders are supplemented with red cells. The following statement illustrates conflict: “Based on the eligibility and exclusion criteria of our study, and on the haemoglobin and haematocrit values reported here, we are confident that immediate cord clamping did not cause significant blood losses in the great majority of our cases.” Blood loss into the placenta is silent, invisible and occasionally massive. Hemoglobin and hematocrit values near birth (or at the time of acute hemorrhage) have no relation at all to circulating blood volume or to blood loss and are usually misleading (as in dehydration – high hematocrit, low blood volume.) Taken two weeks post-partum after hemo- dilution, they do reflect blood loss during delivery. “Sick neonates are one of the most heavily transfused groups of patients in modern medicine.” [3] The neonatal criterion for transfusion (of red cells only) is Hg<10 gms/dl; the blood plasma volume (40% of total blood volume) has been restored by the child over a period of days / weeks. A Hg<10 gms/dl at one+ weeks of life indicates major blood loss at birth and a major error in blood volume management, or in cord clamping. Even in preemies, blood draws do not remove 40% of blood volume. These hypovolemic neonates after birth are hypotensive, oliguric, pale, hypothermic and many exhibit retraction respiration. “In our experience term infants can tolerate acute blood losses of up to 40 percent of blood volume.” Professor Peltonen [4] agrees with Professor Shah, but recommends against it. Most parents would not consent to the practice. Regarding Professor Peltonen’s review, [4] the exact quotation in a paragraph devoted to “clamping before the first breath” is: “It would seem that the closing of the umbilical circulation before the aeration of the lungs has taken place is a highly unphysiological measure, which should thus be avoided. Although the normal infant survives without harm, in certain unfavourable circumstances, the consequences may be fatal.” Peltonen concludes the paragraph with: “There is thus good reason in cases of resuscitation to keep the placental circulation intact.” Profesor Shah’s response makes no mention of retraction respiration (RR) that is an integral part of my postulation that hypovolemia and deficient perfusion of brain tissue are the primary cause of neuron necrosis. In the adverse outcome group, 69 of 80 neonates had defined “pulmonary dysfunction.” If all those neonates had RR, they all were hypovolemic at birth. Record review should be able to settle the question of this common and frequently misunderstood symptom in the “risk” neonate. Regarding hyperviscosity and polycythemia, neither is pathological in the normovolemic child. The basic concept of the “hyperviscosity syndrome” is pathology caused by inadequate perfusion of tissues – “sticky blood” causing diminished blood flow through vessels. Blood flow (perfusion) is inversely proportional to viscosity, directly proportional to the pressure differential (blood pressure) and proportional to the fourth power of the diameter of the vessel. (Arteriole) Thus an adequate blood pressure alone should counteract increased viscosity; vaso- dilatation from 1 to 2 increases perfusion 16 times! Vaso-dilatation from 1 to 1.2 doubles perfusion. Rapid hydration of the intra-uterine asphyxiated, dehydrated, polycythemic, hyperviscous neonate will dilate the arterioles and prevent the hyperviscosity syndrome. Fortunately nowadays, amnio-infusion usually corrects the pathology prior to birth. The “hyperviscosity syndrome” is the product of hypovolemia, hemoconcentration and primarily, vasoconstriction. Professor Shah’s statement “ it is likely that the umbilical cord had lost its function in the great majority of our cases by the time that the cord was clamped.” is contradicted by one of the eligibility criteria in the original study – “metabolic acidosis (cord arterial blood or blood gas analysis within the first hour after birth) indicated by a base deficit >16mmol/l”. This blood is obtained routinely on “risk” neonates from cord arteries by immediate cord clamping. [5] A cord that has lost its function has no available blood in the arteries. All cases with cord arterial blood analysis had actively functioning cords. Myocardial contractility is dependent on an oxygenated blood supply; hypoxia at some degree stops the heartbeat, and, after this point, infarction of all tissues will occur. A pulsating cord indicates that functional cardiac oxygenation and viable tissue perfusion are still active. Whatever pathology and dysfunction is present in a “cord compressed” neonate with a pulsating cord, placental function is, and has been maintaining life. That placental function should be used to maintain life, correct pathology and dysfunction, and supplement resuscitation during the third stage of labor. Overall, in managing the cord-compressed, “asphyxiated” neonate, there appears to be a consensus that leaving a pulsating cord alone to the point of spontaneous closure of the cord vessels, (allowing placental function to restore physiology,) and using immediate clamping of an obviously mal-functioning cord to facilitate neonatal correction of pathologies are beneficial for optimal survival. With this agreement, disputes over transfusion and placental function become moot. Correction of the present situation demands that obstetrical and neonatal management of the risk neonate concur and overlap. Placental respiration normally continues until pulmonary respiration is established. Oxygenation of aortic blood closes the umbilical arteries. Do the two specialties have to have a wall of cord clamps between their turfs? At c-section, would not placental transfusion (generated by uterine contraction) be handled best by the obstetrician while the neonatologist is managing the receiving end? “To our knowledge, a comprehensive health outcome has not been studied in relation to placental transfusion.” This enormous “gap” in perinatal knowledge is readily closed. On the premise that physiological cord closure results in a physiological blood volume, several hundred normal (preemie and term) deliveries should be allowed to proceed through the third stage of labor without severing the cord until the placenta is delivered. (Many midwives do this routinely.) Gunther’s method of continuous weight recording [6] to measure placental transfusion could be done on many selected cases. Placental and neonatal blood studies and urine output are recorded; as are blood pressure, pulse and respiration rates, oxygen saturation, suckling, weight change etc. One or two MRI studies on the brain would be invaluable in providing radiologists with records of normal perfusion of the neonatal brain. By establishing these standards and parameters – physiological norms – correction of abnormalities in the compromised neonate is greatly facilitated and put on a rational, objective basis. Professor Shah and his colleagues are in a unique position to accomplish this goal of optimal neonatal resuscitation. References (1). Linderkamp O. Placental transfusion: determinants and effects. Clinics in Perinatology 1982;9:559-592 (2). Morley GM. Letters to the Editor. OBSTETRICS & GYNECOLOGY Vol.97 No. 6 June 2001 1024. (3). N A Murray and I A G Roberts. Neonatal transfusion practice Arch. Dis. Child. Fetal Neonatal Ed., Mar 2004; 89: F101 – 107 (4). Peltonen T. Placental Transfusion, Advantage - Disadvantage. Eur J Pediatr. 1981;137:141-146 (5). ACOG Committee Opinion Number 138 - April 1994, published in the International Journal of Gynaecology and Obstetrics 45:303-304 [54], reaffirmed 2000, and listed as current in OBSTETRICS & GYNECOLOGY, February 2002 (6). Gunther M. The transfer of blood between the baby and the placenta in the minutes after birth. Lancet 1957;I:1277-1280.